Sulfonamide and sulfamide substituted imidazoquinolines

ABSTRACT

Imidazoquinoline and tetrahydroimidazoquinoline compounds that contain sulfonamide or sulfonamide functionality at the 1-position are useful as immune response modifiers. The compounds and compositions of the invention can induce the biosynthesis of various cytokines and are useful in the treatment of a variety of conditions including viral diseases and neoplastic diseases.

FIELD OF THE INVENTION

[0001] This invention relates to imidazoquinoline compounds that havesulfonamide or sulfamide substitution at the 1-position and topharmaceutical compositions containing the compounds. A further aspectof this invention relates to the use of these compounds asimmunomodulators, for inducing cytokine biosynthesis in animals and inthe treatment of diseases including viral and neoplastic diseases.

BACKGROUND OF THE INVENTION

[0002] The first reliable report on the 1H-imidazo[4,5-c]quinoline ringsystem, Backman et al., J. Org. Chem. 15, 1278-1284 (1950) describes thesynthesis of1-(6-methoxy-8-quinolinyl)-2-methyl-1H-imidazo[4,5-c]quinoline forpossible use as an antimalarial agent. Subsequently, syntheses ofvarious substituted 1H-imidazo[4,5-c]quinolines were reported. Forexample, Jain et al., J. Med. Chem. 11, pp. 87-92 (1968), synthesizedthe compound 1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline as apossible anticonvulsant and cardiovascular agent. Also, Baranov et al.,Chem. Abs. 85, 94362 (1976), have reported several2-oxoimidazo[4,5-c]quinolines, and Berenyi et al., J. Heterocyclic Chem.18, 1537-1540 (1981), have reported certain2-oxoimidazo[4,5-c]quinolines.

[0003] Certain 1H-imidazo[4,5-c]quinolin-4-amines and 1- and2-substituted derivatives thereof were later found to be useful asantiviral agents, bronchodilators and immunomodulators. These aredescribed in, inter alia, U.S. Pat. Nos. 4,689,338; 4,698,348;4,929,624; 5,037,986; 5,268,376; 5,346,905; and 5,389,640, all of whichare incorporated herein by reference.

[0004] There continues to be interest in the imidazoquinoline ringsystem, as seen for example in WO 98/30562, EP 894 797 and WO 00/09506.EP 894 797 discloses amide substituted imidazoquinoline compounds thatare disclosed to be useful as immune response modifying compounds, whileWO 00/09506 discloses imidazoquinoline compounds that contain asulfonamide substituent wherein the sulfonamide nitrogen is part of asaturated heterocyclic ring. Despite these efforts, however, there is acontinuing need for compounds that have the ability to modulate theimmune response, by induction of cytokine biosynthesis or othermechanisms.

SUMMARY OF THE INVENTION

[0005] We have found a new class of compounds that are useful ininducing cytokine biosynthesis in animals. Accordingly, this inventionprovides compounds of Formula I:

[0006] wherein R, R₁ and R₂ are as defined herein.

[0007] The compounds of Formula I are useful as immune responsemodifiers due to their ability to induce cytokine biosynthesis andotherwise modulate the immune reponse when administered to animals. Thismakes the compounds useful in the treatment of a variety of conditionssuch as viral diseases and tumors that are responsive to such changes inthe immune response.

[0008] The invention further provides pharmaceutial compositionscontaining a therapeutically effective amount of a compound of Formula Iand methods of inducing cytokine biosynthesis in an animal, treating aviral infection and/or treating a neoplastic disease in an animal byadministering a effective amount of a compound of Formula I to theanimal.

[0009] In addition, methods of synthesizing compounds of Formula I andintermediates useful in the synthesis of these compounds are provided.

DETAILED DESCRIPTION OF THE INVENTION

[0010] As mentioned earlier, the invention provides compounds of FormulaI:

[0011] wherein

[0012] R₁ is -alkyl-NR₃—SO₂—X—R₄ or -alkenyl-NR₃—SO₂—X—R₄;

[0013] X is a bond or —NR₅—;

[0014] R₄ is aryl, heteroaryl, heterocyclyl, alkyl or alkenyl, each ofwhich may be unsubstituted or substituted by one or more substituentsselected from the group consisting of:

[0015] -alkyl;

[0016] -alkenyl;

[0017] -aryl;

[0018] -heteroaryl;

[0019] -heterocyclyl;

[0020] -substituted aryl;

[0021] -substituted heteroaryl;

[0022] -substituted heterocyclyl;

[0023] —O-alkyl;

[0024] —O-(alkyl)₀₋₁-aryl;

[0025] —O-(alkyl)₀₋₁-substituted aryl;

[0026] —O-(alkyl)₀₋₁-heteroaryl;

[0027] —O-(alkyl)₀₋₁-substituted heteroaryl;

[0028] —O-(alkyl)₀₋₁-heterocyclyl;

[0029] —O-(alkyl)₀₋₁-substituted heterocyclyl;

[0030] —COOH;

[0031] —CO—O-alkyl;

[0032] —CO-alkyl;

[0033] —S(O)₀₋₂-alkyl;

[0034] —S(O)₀₋₂-(alkyl)₀₋₁-aryl;

[0035] —S(O)₀₋₂ -(alkyl)₀₋₁-substituted aryl;

[0036] —S(O)₀₋₂ -(alkyl)₀₋₁-heteroaryl;

[0037] —S(O)₀₋₂-(alkyl)₀₋₁-substituted heteroaryl;

[0038] —S(O)₀₋₂-(alkyl)₀₋₁-heterocyclyl;

[0039] —S(O)₀₋₂-(alkyl)₀₋₁-substituted heterocyclyl;

[0040] -(alkyl)₀₋₁-NR₃R₃;

[0041] -(alkyl)₀₋₁-NR₃—CO—O-alkyl;

[0042] -(alkyl)₀₋₁-NR₃—CO-alkyl;

[0043] -(alkyl)₀₋₁-NR₃—CO-aryl;

[0044] -(alkyl)₀₋₁-NR₃—CO-substituted aryl;

[0045] -(alkyl)₀₋₁-NR₃—CO-heteroaryl;

[0046] -(alkyl)₀₋₁-NR₃—CO-substituted heteroaryl;

[0047] —N₃;

[0048] -halogen;

[0049] -haloalkyl;

[0050] -haloalkoxy;

[0051] —CO-haloalkoxy;

[0052] —NO₂;

[0053] —CN;

[0054] —OH;

[0055] —SH; and in the case of alkyl, alkenyl, or heterocyclyl, oxo;

[0056] R₂ is selected from the group consisting of:

[0057] -hydrogen;

[0058] -alkyl;

[0059] -alkenyl;

[0060] -aryl;

[0061] -substituted aryl;

[0062] -heteroaryl;

[0063] -substituted heteroaryl;

[0064] alkyl-O-alkyl;

[0065] alkyl-O-alkenyl; and

[0066] alkyl or alkenyl substituted by one or more substituents selectedfrom the group consisting of:

[0067] —OH;

[0068] -halogen;

[0069] —N(R₃)₂;

[0070] —CO—N(R₃)₂;

[0071] —CO—C₁₋₁₀ alkyl;

[0072] —CO—O—C₁₋₁₀ alkyl;

[0073] —N₃;

[0074] -aryl;

[0075] -substituted aryl;

[0076] -heteroaryl;

[0077] -substituted heteroaryl;

[0078] -heterocyclyl;

[0079] -substituted heterocyclyl;

[0080] —CO-aryl;

[0081] —CO-(substituted aryl);

[0082] —CO-heteroaryl; and

[0083] —CO-(substituted heteroaryl);

[0084] each R₃ is independently selected from the group consisting ofhydrogen and C₁₋₁₀ alkyl;

[0085] R₅ is selected from the group consisting of hydrogen and C₁₋₁₀alkyl, or R₄ and R₅ can combine to form a 3 to 7 membered heterocyclicor substituted heterocyclic ring;

[0086] n is 0 to 4 and each R present is independently selected from thegroup consisting of C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, halogen andtrifluoromethyl,

[0087] or a pharmaceutically acceptable salt thereof.

[0088] Preparation of the Compounds

[0089] Imidazoquinolines of the invention can be prepared according toReaction Scheme I where R, R₁, R₂ and n are as defined above.

[0090] In step (1) of Reaction Scheme I a 4-chloro-3-nitroquinoline ofFormula II is reacted with an amine of Formula R₁NH₂ where R₁ is asdefined above to provide a 3-nitroquinolin-4-amine of Formula III. Thereaction can be carried out by adding amine to a solution of a compoundof Formula II in a suitable solvent such as chloroform ordichloromethane and optionally heating. Many quinolines of Formula IIare known compounds (see for example, U.S. Pat. No. 4,689,338 andreferences cited therein).

[0091] In step (2) of Reaction Scheme I a 3-nitroquinolin-4-amine ofFormula III is reduced to provide a quinoline-3,4-diamine of Formula IV.Preferably, the reduction is carried out using a conventionalheterogeneous hydrogenation catalyst such as platinum on carbon orpalladium on carbon. The reaction can conveniently be carried out on aParr apparatus in a suitable solvent such as isopropyl alcohol ortoluene.

[0092] In step (3) of Reaction Scheme I a quinoline-3,4-diamine ofFormula IV is reacted with a carboxylic acid or an equivalent thereof toprovide a 1H-imidazo[4,5-c]quinoline of Formula V. Suitable equivalentsto carboxylic acid include acid halides, orthoesters, and1,1-dialkoxyalkyl alkanoates. The carboxylic acid or equivalent isselected such that it will provide the desired R₂ substituent in acompound of Formula V. For example, triethyl orthoformate will provide acompound where R₂ is hydrogen and triethyl orthoacetate will provide acompound where R₂ is methyl. The reaction can be run in the absence ofsolvent or in an inert solvent such as toluene. The reaction is run withsufficient heating to drive off any alcohol or water formed as abyproduct of the reaction.

[0093] In step (4) of Reaction Scheme I a 1H-imidazo[4,5-c]quinoline ofFormula V is oxidized to provide a 1H-imidazo[4,5-c]quinoline-5N-oxideof Formula VI using a conventional oxidizing agent that is capable offorming N-oxides. Preferred reaction conditions involve reacting asolution of a compound of Formula V in chloroform with3-chloroperoxybenzoic acid at ambient conditions.

[0094] In step (5) of Reaction Scheme I a1H-imidazo[4,5-c]quinoline-5N-oxide of Formula VI is aminated to providea 1H-imidazo[4,5-c]quinolin-4-amine of Formula VII which is a subgenusof Formula I. Step (5) involves (i) reacting a compound of Formula VIwith an acylating agent and then (ii) reacting the product with anaminating agent. Part (i) of step (5) involves reacting an N-oxide ofFormula VI with an acylating agent. Suitable acylating agents includealkyl- or arylsulfonyl chlorides (e.g., benezenesulfonyl chloride,methanesulfonyl chloride, p-toluenesulfonyl chloride). Arylsulfonylchlorides are preferred. Para-toluenesulfonyl chloride is mostpreferred. Part (ii) of step (5) involves reacting the product of part(i) with an excess of an aminating agent. Suitable aminating agentsinclude ammonia (e.g., in the form of ammonium hydroxide) and ammoniumsalts (e.g., ammonium carbonate, ammonium bicarbonate, ammoniumphosphate). Ammonium hydroxide is preferred. The reaction is preferablycarried out by dissolving the N-oxide of Formula VI in an inert solventsuch as dichloromethane, adding the aminating agent to the solution, andthen slowly adding the acylating agent. The product or apharmaceutically acceptable salt thereof can be isolated usingconventional methods.

[0095] Alternatively, step (5) may be carried out by (i) reacting anN-oxide of Formula VI with an isocyanate and then (ii) hydrolyzing theresulting product. Part (i) involves reacting the N-oxide with anisocyanate wherein the isocyanato group is bonded to a carbonyl group.Preferred isocyanates include trichloroacetyl isocyanate and aroylisocyanates such as benzoyl isocyanate. The reaction of the isocyanatewith the N-oxide is carried out under substantially anhydrous conditionsby adding the isocyanate to a solution of the N-oxide in an inertsolvent such as chloroform or dichloromethane. Part (ii) involveshydrolysis of the product from part (i). The hydrolysis can be carriedout by conventional methods such as heating in the presence of water ora lower alkanol optionally in the presence of a catalyst such as analkali metal hydroxide or lower alkoxide.

[0096] Compounds of the invention where the R₁ substituent contains asulfonamide can also be prepared according to Reaction Scheme II whereR, R₂, R₄ and n are as defined above and m is 1-20.

[0097] In Reaction Scheme II an aminoalkyl substituted1H-imidazo[4,5-c]quinolin-4-amine of Formula VIII is reacted with asulfonyl chloride of Formula IX to provide a compound of Formula X whichis a subgenus of Formula I. The reaction can be run at ambienttemperature in an inert solvent such as dichloromethane in the presenceof a base such as pyridine or N,N-diisopropylethylamine. Many1H-imidazo[4,5-c]quinolin-4-amines of Formula VIII are known compounds,see for example U.S. Pat. No. 6,069,149 (Namba); others can be readilyprepared using known synthetic methods. Many sulfonyl chlorides ofFormula IX are commercially available; others can be readily preparedusing known synthetic methods. The product or a pharmaceuticallyacceptable salt thereof can be isolated using conventional methods.

[0098] Compounds of the invention where the R₁ substituent contains asulfonamide can also be prepared according to Reaction Scheme III whereR, R₂, R₄ and n are as defined above and m is 1-20.

[0099] In Reaction Scheme III an aminoalkyl substituted1H-imidazo[4,5-c]quinolin-4-amine of Formula VIII is reacted with asulfonic anhydride of Formula XI to provide a compound of Formula Xwhich is a subgenus of Formula I. The reaction can be run at ambienttemperature in an inert solvent such as dichloromethane in the presenceof a base such as pyridine or N,N-diisopropylethylamine. Alternatively,the reaction can be run at ambient temperature in acetonitrile. Manysulfonic anhydrides of Formula XI are commercially available; others canbe readily prepared using known synthetic methods. The product or apharmaceutically acceptable salt thereof can be isolated usingconventional methods.

[0100] Tertiary sulfonamides of the invention can be prepared accordingto Reaction Scheme IV where R, R₂, R₃, R₄ and n are as defined above andm is 1-20.

[0101] In Reaction Scheme IV a 1H-imidazo[4,5-c]quinolinyl sulfonamideof Formula X is reacted with a halide of Formula XII to provide acompound of Formula XIII which is a subgenus of Formula I. The reactioncan be carried out at ambient temperature by adding sodium hydride to asolution of a compound of Formula X in N,N-dimethylformamide and thenadding the halide. Many halides of Formula XII are commerciallyavailable; others can be readily prepared using known synthetic methods.The product or a pharmaceutically acceptable salt thereof can beisolated using conventional methods.

[0102] Compounds of the invention where R₁ contains a sulfamide groupcan be prepared according to Reaction Scheme V wherein R, R₂, R₄, R₅ andn are as defined above and m is 1-20.

[0103] In step (1) of Reaction Scheme V an aminoalkyl substituted1H-imidazo[4,5-c]quinolin-4-amine of Formula VIII is reacted withsulfuryl chloride to generate in situ a sulfamoyl chloride of FormulaXIV. The reaction can be carried out by adding a solution of sulfurylchloride in dichloromethane to a solution of a compound of Formula VIIIin dichloromethane in the presence of one equivalent of4-(dimethylamino)pyridine. The reaction is preferably carried out at areduced temperature (−78° C.). Optionally, after the addition iscomplete the reaction mixture can be allowed to warm to ambienttemperature.

[0104] In step (2) of Reaction Scheme V an amine of Formula R₅R₄NH isreacted with the sulfamoyl chloride of Formula XIV to provide a1H-imidazo[4,5-c]quinolinyl sulfamide of Formula XV which is a subgenusof Formula I. The reaction can be carried out by adding a solutioncontaining 2 equivalents of the amine and 2 equivalents of triethylaminein dichloromethane to the reaction mixture from step (1). The additionis preferably carried out at a reduced temperature (−78° C.). After theaddition is complete the reaction mixture can be allowed to warm toambient temperature. The product or a pharmaceutically acceptable saltthereof can be isolated using conventional methods.

[0105] Tetrahydroimidazoquinolines of the invention can be preparedaccording to Reaction Scheme VI where R₂, R₃, R₄, and R₅ are as definedabove and m is 1-20.

[0106] In step (1) of Reaction Scheme VI an aminoalkyl substituted1H-imidazo[4,5-c]quinolin-4-amine of Formula XVI is reduced to providean aminoalkyl substituted6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine of Formula XVII.Preferably the reduction is carried out by suspending or dissolving thecompound of Formula XVI in trifluoroacetic acid, adding a catalyticamount of platinum (IV) oxide, and then subjecting the mixture tohydrogen pressure. The reaction can conveniently be carried out on aParr apparatus. The product or a salt thereof can be isolated usingconventional methods.

[0107] In step (2a) of Reaction Scheme VI an aminoalkyl substituted6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine of Formula XVII isreacted to provide a compound of Formula XVIII which is a subgenus ofFormula I. When R₃ is hydrogen, the reaction can be carried out in onestep according to the methods described in Reaction Schemes. II and IIIabove using a tetrahydroimidazoquinoline of Formula XVII in place of theimidazoquinoline of Formula VIII. When R₃ is other than hydrogen, thereaction can be carried out in two steps with step one being carried outaccording to the methods of Reaction Schemes II and III and step twobeing carried out according to the method of Reaction IV using thetetrahydroimidazoquinoline analog of the imidazoquinoline. The productor a pharmaceutically acceptable salt thereof can be isolated usingconventional methods.

[0108] In step (2b) of Reaction Scheme VI an aminoalkyl substituted6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine of Formula XVII isreacted to provide a compound of Formula XIX which is a subgenus ofFormula I. The reaction can be carried out according to the methoddescribed in Reaction Scheme V using a tetrahydroimidazoquinoline ofFormula XVII in place of the imidazoquinoline of Formula VIII. Theproduct or a pharmaceutically acceptable salt thereof can be isolatedusing conventional methods.

[0109] Tetrahydroimidazoquinolines of the invention can also be preparedaccording to Reaction Scheme VII where R, R₂, R₃, R₄, R₅ and n are asdefined above and m is 1-20.

[0110] In step (1) of Reaction Scheme VII a6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolinyl tert-butylcarbamate ofFormula XX is hydrolyzed to provide an aminoalkyl substituted6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine of Formula XXI. Thereaction can be carried out dissolving the compound of Formula XX in amixture of trifluoroacetic acid and acetonitrile and stirring at ambienttemperature. Alternatively, the compound of Formula XX can be combinedwith dilute hydrochloric acid and heated on a steam bath.Tetrahydro-1H-imidazo[4,5-c]quinolinyl tert-butylcarbamates of FormulaXX can be prepared using the synthetic route disclosed in U.S. Pat. No.5,352,784 (Nikolaides). The product or a salt thereof can be isolatedusing conventional methods.

[0111] Steps (2a) and (2b) can be carried out in the same manner as inReaction Scheme VI.

[0112] Some compounds of Formula I can be readily prepared from othercompounds of Formula I. For example, compounds wherein the R₄substituent contains a chloroalkyl group can be reacted with an amine toprovide an R₄ substituent substituted by a secondary or teriary aminogroup; compounds wherein the R₄ substituent contains a nitro group canbe reduced to provide a compound wherein the R₄ substituent contains aprimary amine.

[0113] As used herein, the terms “alkyl”, “alkenyl”, “alkynyl” and theprefix “-alk” are inclusive of both straight chain and branched chaingroups and of cyclic groups, i.e. cycloalkyl and cycloalkenyl. Unlessotherwise specified, these groups contain from 1 to 20 carbon atoms,with alkenyl and alkynyl groups containing from 2 to 20 carbon atoms.Preferred groups have a total of up to 10 carbon atoms. Cyclic groupscan be monocyclic or polycyclic and preferably have from 3 to 10 ringcarbon atoms. Exemplary cyclic groups include cyclopropyl, cyclopentyl,cyclohexyl and adamantyl.

[0114] The term “haloalkyl” is inclusive of groups that are substitutedby one or more halogen atoms, including groups wherein all of theavailable hydrogen atoms are replaced by halogen atoms. This is alsotrue of groups that include the prefix “haloalk-”. Examples of suitablehaloalkyl groups are chloromethyl, trifluoromethyl, and the like.

[0115] The term “aryl” as used herein includes carbocyclic aromaticrings or ring systems. Examples of aryl groups include phenyl, naphthyl,biphenyl, fluorenyl and indenyl. The term “heteroaryl” includes aromaticrings or ring systems that contain at least one ring hetero atom (e.g.,O, S, N). Suitable heteroaryl groups include furyl, thienyl, pyridyl,quinolinyl, tetrazolyl, imidazo, pyrazolo, thiazolo, oxazolo, and thelike.

[0116] “Heterocyclyl” includes non-aromatic rings or ring systems thatcontain at least one ring hetero atom (e.g., O, S, N). Exemplaryheterocyclic groups include pyrrolidinyl, tetrahydrofuranyl,morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, thiazolidinyl,imidazolidinyl, and the like.

[0117] Unless otherwise specified, the terms “substituted cycloalkyl”,“substituted aryl”, “substituted heteroaryl” and “substitutedheterocyclyl” indicate that the rings or ring systems in question arefurther substituted by one or more substituents independently selectedfrom the group consisting of alkyl, alkoxy, alkylthio, hydroxy, halogen,haloalkyl, haloalkylcarbonyl, haloalkoxy (e.g., trifluoromethoxy),nitro, alkylcarbonyl, alkenylcarbonyl, arylcarbonyl, heteroarylcarbonyl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl,heterocycloalkyl, nitrile, alkoxycarbonyl, alkanoyloxy, alkanoylthio,and in the case of cycloalkyl and heterocyclyl, oxo.

[0118] In structural formulas representing compounds of the inventioncertain bonds are represented by dashed lines. These lines mean that thebonds represented by the dashed line can be present or absent.Accordingly, compounds of Formula I can be either imidazoquinolinecompounds or tetrahydroimidazoquinoline compounds.

[0119] The invention is inclusive of the compounds described herein inany of their pharmaceutically acceptable forms, including isomers suchas diastereomers and enantiomers, salts, solvates, polymorphs, and thelike.

[0120] Pharmaceutical Compositions and Biological Activity

[0121] Pharmaceutical compositions of the invention contain atherapeutically effective amount of a compound of Formula I incombination with a pharmaceutically acceptable carrier.

[0122] As used herein, the term “a therapeutically effective amount”means an amount of the compound sufficient to induce a therapeuticeffect, such as cytokine induction, antitumor activity and/or antiviralactivity. Although the exact amount of active compound used in apharmaceutical composition of the invention will vary according tofactors known to those of skill in the art, such as the physical andchemical nature of the compound as well as the nature of the carrier andthe intended dosing regimen, it is anticipated that the compositions ofthe invention will contain sufficient active ingredient to provide adose of about 100 ng/kg to about 50 mg/kg, preferably about 10 μg/kg toabout 5 mg/kg of the compound to the subject. Any of the conventionaldosage forms may be used, such as tablets, lozenges, parenteralformulations, syrups, creams, ointments, aerosol formulations,transdermal patches, transmucosal patches and the like.

[0123] The compounds of the invention have been shown to induce theproduction of certain cytokines in experiments performed according tothe tests set forth below. These results indicate that the compounds areuseful as immune response modifiers that can modulate the immuneresponse in a number of different ways, rendering them useful in thetreatment of a variety of disorders.

[0124] Cytokines that may be induced by the administration of compoundsaccording to the invention generally include interferon-α (IFN-α) andtumor necrosis factor-α (TNF-α) as well as certain interleukins (IL).Cytokines whose biosynthesis may be induced by compounds of theinvention include IFN-α, TNF-α, IL-1, 6, 10 and 12, and a variety ofother cytokines. Among other effects, cytokines inhibit virus productionand tumor cell growth, making the compounds useful in the treatment ofviral diseases and tumors.

[0125] In addition to the ability to induce the production of cytokines,the compounds of the invention affect other aspects of the innate immuneresponse. For example, natural killer cell activity may be stimulated,an effect that may be due to cytokine induction. The compounds may alsoactivate macrophages, which in turn stimulates secretion of nitric oxideand the production of additional cytokines. Further, the compounds maycause proliferation and differentiation of B-lymphocytes.

[0126] Compounds of the invention also have an effect on the acquiredimmune response. For example, although there is not believed to be anydirect effect on T cells or direct induction of T cell cytokines, theproduction of the T helper type 1 (Th1) cytokine IFN-γ is inducedindirectly and the production of the T helper type 2 (Th2) cytokinesIL-4, IL-5 and IL-13 are inhibited upon administration of the compounds.This activity means that the compounds are useful in the treatment ofdiseases where upregulation of the Th1 response and/or downregulation ofthe Th2 response is desired. In view of the ability of compounds ofFormula Ia to inhibit the Th2 immune response, the compounds areexpected to be useful in the treatment of atopic diseases, e.g., atopicdermatitis, asthma, allergy, and allergic rhinitis; and systemic lupuserythematosis; as a vaccine adjuvant for cell mediated immunity; andpossibly as a treatment for recurrent fungal diseases and chlamydia.

[0127] The immune response modifying effects of the compounds make themuseful in the treatment of a wide variety of conditions. Because oftheir ability to induce the production of cytokines such as IFN-α and/orTNF-α, the compounds are particularly useful in the treatment of viraldiseases and tumors. This immunomodulating activity suggests thatcompounds of the invention are useful in treating diseases such as, butnot limited to, viral diseases including genital warts; common warts;plantar warts; Hepatitis B; Hepatitis C; Herpes Simplex Virus Type I andType II; molluscum contagiosum; HIV; CMV; VZV; intraepithelialneoplasias such as cervical intraepithelial neoplasia; humanpapillomavirus (HPV) and associated neoplasias; fungal diseases, e.g.candida, aspergillus, and cryptococcal meningitis; neoplastic diseases,e.g., basal cell carcinoma, hairy cell leukemia, Kaposi's sarcoma, renalcell carcinoma, squamous cell carcinoma, myelogenous leukemia, multiplemyeloma, melanoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma,and other cancers; parasitic diseases, e.g. pneumocystis carnii,cryptosporidiosis, histoplasmosis, toxoplasmosis, trypanosome infection,leishmaniasis; and bacterial infections, e.g., tuberculosis,mycobacterium avium. Additional diseases or conditions that can betreated using the compounds of the invention include eczema;eosinophilia; essential thrombocythaemia; leprosy; multiple sclerosis;Ommen's syndrome; discoid lupus; Bowen's disease; Bowenoid papulosis;and to enhance or stimulate the healing of wounds, including chronicwounds.

[0128] Accordingly, the invention provides a method of inducing cytokinebiosynthesis in an animal comprising administering an effective amountof a compound of Formula I to the animal. An amount of a compoundeffective to induce cytokine biosynthesis is an amount sufficient tocause one or more cell types, such as monocytes, macrophages, dendriticcells and B-cells to produce an amount of one or more cytokines such as,for example, IFN-<, TNF-<, IL-1,6,10 and 12 that is increased over thebackground level of such cytokines. The precise amount will varyaccording to factors known in the art but is expected to be a dose ofabout 100 ng/kg to about 50 mg/kg, preferably about 110 μg/kg to about 5mg/kg. The invention also provides a method of treating a viralinfection in an animal, and a method of treating a neoplastic disease inan animal, comprising administering an effective amount of a compound ofFormula I to the animal. An amount effective to treat or inhibit a viralinfection is an amount that will cause a reduction in one or more of themanifestations of viral infection, such as viral lesions, viral load,rate of virus production, and mortality as compared to untreated controlanimals. The precise amount will vary according to factors known in theart but is expected to be a dose of 100 ng/kg to about 50 mg/kg,preferably about 10 μg/kg to about 5 mg/kg. An amount of a compoundeffective to treat a neoplastic condition is an amount that will cause areduction in tumor size or in the number of tumor foci. Again, theprecise amount will vary according to factors known in the art but isexpected to be a dose of about 100 ng/kg to about 50 mg/kg, preferablyabout 10 μg/kg to about 5 mg/kg.

[0129] The invention is further described by the following examples,which are provided for illustration only and are not intended to belimiting in any way.

EXAMPLE 1N¹-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-5-(dimethylamino)-1-naphthalenesulfonamide

[0130]

[0131] 5-Dimethylamino-1-naphthalenesulfonyl chloride (1.82 g, 6.74mmol) was added to a mixture of N,N-diisopropylethylamine (1.23 mL, 7.06mmol), dichloromethane (15 mL) and1-(4-aminobutyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (2.0 g, 6.42mmol). The reaction mixture was allowed to stir at ambient temperatureovernight. Methanol was added to the reaction mixture until a clearsolution was obtained. Silica gel was added to the reaction mixture andthen the solvents were removed. The silica gel was placed in a columnand then eluted with chloroform in a stepwise gradient to 9:1chloroform:methanol. The resulting product was recrystallized fromN,N-dimethylformamide and deionized water to provide 2.5 g ofN¹-[4-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-5-(dimethylamino)-1-naphthalenesulfonamideas a yellow crystalline solid, m.p. 223-224° C. Analysis: Calculated forC₃₀H₃₆N₆O₂S: % C, 66.15; % H, 6.66; % N, 15.43; Found: % C, 66.36; % H,6.34; % N, 15.23.

EXAMPLE 2N¹-[4-(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-5-(dimethylamino)-1-naphthalenesulfonamide

[0132]

[0133] A suspension of1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.5 g, 2.0 mmol) inpyridine (250 mL) was warmed to 60° C. to dissolve the amine. Thesolution was allowed to cool to about 30° C. and then5-dimethylamino-1-naphthalenesulfonyl chloride (0.5 g, 1.8 mmol) wasslowly added. After 1 hour 0.3 g of5-dimethylamino-1-naphthalenesulfonyl chloride was added. The reactionmixture was warmed to 60° C. and maintained at that temperatureovernight. The reaction mixture was concentrated under vacuum. Theresidue was recrystallized from propyl acetate to provideN¹-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-5-(dimethylamino)-1-naphthalenesulfonamideas a solid, m.p. 200-201° C.

EXAMPLE 3N²-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2-thiophenesulfonamide

[0134]

[0135] 2-Thiophenesulfonyl chloride (0.3 g in 10 ml dichloromethane, 1.6mmol) was added dropwise to a stirring solution of1-(4-aminobutyl)-2-butyl-1H-imidazo[4,5-c]quinoline-4-amine (0.5 g, 1.6mmol), dichloromethane (40 ml), and pyridine (0.8 ml). The reaction wasmaintained at room temperature for a few hours and then an additionalportion of 2-thiophenesulfonyl chloride (0.1 g, 0.6 mmol) was added. Thereaction was maintained overnight and then concentrated in vacuo. Theresulting residue was purified by flash column chromatography (silicagel, 9:1 dichloromethanemethanol) and the fractions containing productwere washed with saturated aqueous sodium bicarbonate. The organic layerwas dried (MgSO₄), filtered, and concentrated to provide 0.2 g ofN²-[4-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2-thiophenesulfonamideas an off white powder, m.p. 137.5-141.5° C. ¹H NMR (300 MHz, DMSO-d₆) δ8.00 (d, J=8.0 Hz, 1H), 7.89 (dd, J=5.0, 1.3 Hz, 1H), 7.83 (broad s,1H), 7.61 (dd, J=8.3, 1.1 Hz, 1H), 7.54 (dd, J=3.7, 1.3 Hz, 1H), 7.42(t, J=7.2 Hz, 1H), 7.25 (m, 1H), 7.15 (m, 1H), 6.44 (broad s, 2H), 4.47(t, J=7.4 Hz, 2H), 2.87 (m, 4H), 1.80 (m, 4H), 1.58-1.38 (m, 4H), 0.96(t, J=7.4 Hz, 3H); IR (KBr) 3467, 3361, 3167, 3091, 2957, 2933, 2870,1644, 1617, 1585, 1533, 1478, 1405, 1336, 1154, 1095, 1014, 854, 761,733 cm⁻¹; MS (EI) m/e 457.1606 (457.1606 calcd for C₂₂H₂₇N₅O₂S₂); Analcalcd for C₂₂H₂₇N₅O₂S₂: C, 57.74; H, 5.95; N, 15.30. Found: C, 57.50; H,5.98; N, 15.15.

EXAMPLE 4N-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]phenylmethanesulfonamide

[0136]

[0137] α-Toluenesulfonyl chloride (0.5 g in 10 ml dichloromethane, 2.7mmol) was added dropwise to a stirring solution of1-(4-aminobutyl)-2-butyl-1H-imidazo[4,5-c]quinoline-4-amine (0.75 g, 2.4mmol), dichloromethane (115 ml), and pyridine (1 ml). The reaction wasmaintained at room temperature for 4 hours and then concentrated invacuo. The residue was purified by flash column chromatography (silicagel, 9:1 dichloromethane\methanol, Rf 0.16). The fractions containingproduct were combined and washed with saturated aqueous bicarbonate. Theorganic layer was dried (MgSO4), filtered, and concentrated. A finalrecrystallization from dichloromethane\diethyl ether provided 0.65 g ofN-[4-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]phenylmethanesulfonamideas a white crystalline solid, m.p. 197.0-199.5° C. ¹H NMR (300 MHz,DMSO-d₆) δ 8.02 (d, J=7.6 Hz, 1H), 7.62 (dd, J=8.3, 1.1 Hz, 1H), 7.42(dt, J=7.5, 1.1 Hz, 1H), 7.35-7.23 (m, 7H), 7.12 (t, J=5.4 Hz, 1H), 6.46(broad s, 2H), 4.49 (t, J=7.5 Hz, 2H), 4.29 (s, 2H), 2.91 (m, 4H),1.83-1.42 (m, 8H), 0.96 (t, J=7.4 Hz, 3H); IR (KBr) 3460, 3293, 3226,3158, 2955, 2931, 2867, 1632, 1586, 1534, 1482, 1437, 1389, 1331, 1152,1094, 752, 700 cm⁻¹; MS (EI) m/e 465.2204 (465.2198 calcd forC₂₅H₃₁N₅O₂S); Anal calcd for C₂₅H₃₁N₅O₂S: C, 64.49; H, 6.71; N, 15.04.Found: C, 64.15; H, 6.71; N, 15.00.

EXAMPLE 5N¹-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-1-benzenesulfonamide

[0138]

[0139] Benzenesulfonyl chloride (0.45 ml in 10 ml dichloromethane, 3.5mmol) was added dropwise to a stirring solution of1-(4-aminobutyl)-2-butyl-1H-imidazo[4,5-c]quinoline-4-amine (1.0 g, 3.2mmol), dichloromethane (140 ml), and pyridine (0.8 ml). The reaction wasmaintained at room temperature for four hours and then concentrated invacuo. The residue was purified by flash column chromatography (silicagel, 9:1 dichloromethane\methanol, R_(f) 0.28) followed byrecrystallization from dichloromethane\diethyl ether to provide 1.14 gofN¹-[4-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-1-benzenesulfonamideas a white powder, m.p. 75.5-79.0° C. ¹H NMR (500 MHz, DMSO-d₆) δ 7.99(d, J=7.7 Hz, 1H), 7.76 (d, J=7.2, 2H), 7.63-7.53 (m, 5H), 7.42 (m, 1H),7.25 (m, 1H), 6.43 (broad s, 2H), 4.45 (t, J=7.6 Hz, 2H), 2.87 (t, J=7.7Hz, 2H), 2.78 (m, 2H), 1.79 (m, 4H), 1.55-1.40 (m, 4H), 0.95 (t, J=7.4Hz, 3H); MS (EI) m/e 451.2036 (451.2042 calcd for C₂₄H₂₉N₅O₂S); Analcalcd for C₂₄H₂₉N₅O₂S: C, 63.83; H, 6.47; N, 15.51. Found: C, 63.89; H,6.42; N, 15.30.

EXAMPLE 6N-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamide

[0140]

[0141] Methanesulfonic anhydride (0.6 g, 3.4 mmol) was added dropwise toa stirring solution of1-(4-aminobutyl)-2-butyl-1H-imidazo[4,5-c]quinoline-4-amine (1.0 g, 3.2mmol) and acetonitrile (200 ml). A precipitate formed within a fewminutes. The solvent was removed in vacuo and the residue waspartitioned between dichloromethane and saturated aqueous sodiumbicarbonate. The fractions were separated and the organic fraction wasdried (MgSO₄), filtered and concentrated to yield the crude product as awhite solid. Recrystallization from methyl acetate providedN-[4-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamideas a white crystalline solid, m.p. 195.1-196.0° C. ¹H NMR (300 MHz,DMSO-d₆) δ 8.04 (d, J=7.4 Hz, 1H), 7.61 (dd, J=8.3, 1.2 Hz, 1H), 7.50(dt, J=7.5, 1.1 Hz, 1H), 7.26 (dt, J=7.5, 1.2 Hz, 1H), 6.99 (t, J=5.7Hz, 1H), 6.44 (broad s, 2H), 4.52 (t, J=7.5 Hz, 2H), 3.02-2.86 (m, 7H),1.82 (m, 4H), 1.62 (m, 2H), 1.46 (q, J=7.4 Hz, 2H), 0.96 (t, J=7.4 Hz,3H); IR (KBr) 3348, 3299, 3152, 2952, 2931, 2869, 1642, 1584, 1530,1480, 1323, 1155, 1142, 1094, 982, 765 cm⁻¹; MS (EI) m/e 389.1889(389.1885 calcd for C₁₉H₂₇N₅O₂S); Anal calcd for C₁₉H₂₇N₅O₂S: C, 58.59;H, 6.99; N, 17.98. Found: C, 58.26; H, 6.64; N, 17.69

EXAMPLE 7N¹-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-3-nitro-1-benzenesulfonamideHydrochloride

[0142]

[0143] According to the general method of Example5,3-nitrobenzenesulfonyl chloride and1-(4-aminobutyl)-2-butyl-1H-imidazo[4,5-c]quinoline-4-amine werecombined.N¹-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-3-nitro-1-benzenesulfonamidewas isolated as the hydrochloride salt (white solid), m.p. 176.0-178.2°C. ¹H NMR (300 MHz, DMSO-d₆) δ 8.70 (very broad s, 2H), 8.49-8.42 (m,2H), 8.21-8.17 (m, 2H), 8.06 (t, J=5.7 Hz, 1H), 7.88-7.81 (m, 2H), 7.71(t, J=7.7 Hz, 1H), 7.57 (t, J=7.7 Hz, 1H), 4.56 (t, J=7.3 Hz, 2H), 2.94(t, J=7.7 Hz, 2H), 2.86 (m, 2H), 1.81 (m, 4H), 1.60-1.42 (m, 4H), 0.96(t, J=7.3 Hz, 3H); IR (KBr) 3096, 2954, 2869, 2771, 1671, 1607, 1528,1351, 1335, 1163, 1128, 1083, 879, 758, 735, 672, 661 cm⁻¹; MS (EI) m/e496.1897 (496.1893 calcd for C₂₄H₂₈N₆O₄S). Anal calcd forC₂₄H₂₈N₆O₄S*HCl*H₂O: C, 52.31; H, 5.67; N, 15.25. Found: C, 52.26; H,5.46; N, 15.09.

EXAMPLE 8N¹-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-3-amino-1-benzenesulfonamideHydrochloride

[0144]

[0145] A solution ofN¹-[4-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-3-nitro-1-benzenesulfonamidehydrochloride (0.4 g) in methanol (250 ml) was charged with a catalyticamount of 10% palladium on carbon (0.085 g). The reaction was placedunder an atmosphere of hydrogen (50 psi; 3.44×10⁵ Pa) and shaken on aParr apparatus for 2 hours. The reaction mixture was filtered and thesolvent removed in vacuo. The solid product was recrystallized from2-propanol to provide 0.18 g ofN′-[4-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-3-amino-1-benzenesulfonamidehydrochloride as an off white crystalline solid, m.p. 110.2° C.(decomposition). ¹H NMR (300 MHz, DMSO-d₆) δ 8.70 (very broad s, 2H),8.22 (d, J=8.2 Hz, 1H), 7.83 (d, J=7.8 Hz, 1H), 7.72 (t, J=7.6 Hz, 1H),7:59 (t, J=7.7 Hz, 1H), 7.43 (t, J=5.9 Hz, 1H), 7.15 (t, J=7.9 Hz, 1H),6.95 (t, J=1.9 Hz, 1H), 6.84 (d, J=7.7 Hz, 1H), 6.73 (dd, J=8.0, 1.5 Hz,1H), 5.63 (broad s, 2H), 4.56 (t, J=7.5 Hz, 2H), 2.96 (t, J=7.7 Hz, 2H),2.77 (q, J=6.3 Hz, 2H), 1.83 (m, 4H), 1.60-1.40 (m, 4H), 0.97 (t, J=7.3Hz, 3H); IR (KBr) 3313, 3135, 2957, 2870, 2782, 1671, 1599, 1485, 1454,1313, 1155, 1084, 754, 686 cm⁻¹; MS (EI) m/e 466.2150 (466.2151 calcdfor C₂₄H₃₀N₆O₂S). Anal calcd for C₂₄H₃₀N₆O₂S*HCl*0.25H₂O: C, 56.79; H,6.26; N, 16.56; Cl, 6.98. Found: C, 56.87; H, 6.22; N, 16.19; Cl, 7.22.

EXAMPLE 9N¹-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-4-nitro-1-benzenesulfonamideHydrochloride

[0146]

[0147] According to the general method of Example5,4-nitrobenzenesulfonyl chloride and1-(4-aminobutyl)-2-butyl-1H-imidazo[4,5-c]quinoline-4-amine werecombined.N¹-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-4-nitro-1-benzenesulfonamidewas isolated as the hydrochloride salt (white solid), m.p. 96.0° C.(decomposition). ¹H NMR (300 MHz, DMSO-d₆) δ 8.70 (very broad s, 2H),8.38-8.34 (m, 2H), 8.19 (d, J=8.2 Hz, 1H), 8.09 (t, J=5.6 Hz, 1H),8.03-7.99 (m, 2H), 7.80 (d, J=7.4 Hz, 1H), 7.68 (t, J=7.4 Hz, 1H), 7.54(t, J=7.2 Hz, 1H), 4.55 (t, J=7.4 Hz, 2H), 2.94 (t, J=7.7 Hz, 2H), 2.86(q, J=6.2 Hz, 2H), 1.80 (m, 4H), 1.58 (m, 2H), 1.45 (q, J=7.5 Hz, 2H),0.96 (t, J=7.3 Hz, 3H); IR (KBr) 3283, 3100, 2957, 2870, 2782, 1670,1606, 1528, 1347, 1311, 1162, 1092, 854, 746, 737, 686 cm⁻¹; MS (E1) m/e496.1902 (496.1893 calcd for C₂₄H₂₈N₆O₄S). Anal calcd forC₂₄H₂₈N₆O₄S*HCl*0.85H₂O: C, 52.57; H, 5.64; N, 15.33. Found: C, 52.57;H, 5.46; N, 15.33.

EXAMPLE 10N¹-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-4-amino-1-benzenesulfonamideHydrochloride

[0148]

[0149] A solution ofN′-[4-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-4-nitro-1-benzenesulfonamidehydrochloride (0.38 g) in methanol (250 ml) was charged with a catalyticamount of 10% palladium on carbon (0.085 g). The reaction was placedunder an atmosphere of hydrogen (50 psi; 3.44×10⁵ Pa)) and shaken on aParr apparatus for 2 hours. The reaction mixture was filtered and thesolvent removed in vacuo. The solid product was recrystallized from2-propanol to provide 0.34 g ofN¹-[4-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-4-amino-1-benzenesulfonamidehydrochloride as an off white powder, m.p. 203.1-205.0° C. ¹H NMR (300MHz, DMSO-d₆) δ 8.65 (very broad s, 2H), 8.21 (d, J=8.0 Hz, 1H), 7.82(m, 1H), 7.71 (t, J=7.7 Hz, 1H), 7.58 (t, J=7.7 Hz, 1H), 7.38 (d, J=8.7Hz, 2H), 7.13 (t, J=5.9 Hz, 1H), 6.60 (d, J=8.7 Hz, 2H), 5.92 (broad s,2H), 4.55 (t, J=7.6 Hz, 2H), 2.96 (t, J=7.6 Hz, 2H), 2.70 (q, J=6.4 Hz,2H), 1.81 (m, 4H), 1.58-1.43 (m, 4H), 0.96 (t, J=7.4 Hz, 3H); IR (KBr)3430, 3316, 3215, 3046, 2955, 2868, 2679, 1671, 1594, 1334, 1157, 1091,851, 776, 759 cm⁻¹; MS (EI) m/e 466.2145 (466.2151 calcd forC₂₄H₃₀N₆O₂S). Anal calcd for C₂₄H₃₀N₆O₂S*HCl: C, 57.30; H, 6.21; N,16.71. Found: C, 57.36; H, 6.31; N, 16.21.

EXAMPLE 11N⁵-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-5-isoquinolinesulfonamide

[0150]

[0151] A suspension of isoquinoline-5-sulfonyl chloride hydrochloride(0.83 g in 50 ml of pyridine, 3.1 mmol) was added dropwise to a stirringsolution of 1-(4-aminobutyl)-2-butyl-1H-imidazo[4,5-c]quinoline-4-amine(1.0 g, 3.2 mmol) and dichloromethane (175 ml). The solution turned abright yellow color and was maintained at room temperature for 4 hours.An additional 0.18 g of isoquinoline-5-sulfonyl chloride hydrochloridewas added and the reaction was maintained an additional 60 hours. Theyellow solution was concentrated in vacuo, dissolved in dichloromethane,and washed sequentially with saturated aqueous sodium bicarbonate andwater. The organic fraction was dried (MgSO₄), filtered, andconcentrated in vacuo. The residue was purified by flash columnchromatography (silica gel, 9:1 dichloromethanemethanol) to provide 0.7g ofN⁵-[4-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-5-isoquinolinesulfonamideas a white crystalline solid, m.p. 96.0° C. (decomposition). ¹H NMR (300MHz, DMSO-d₆) δ 9.44 (d, J=0.7 Hz, 1H), 8.64(d, J=6.1 Hz, 1H), 8.41-8.35(m, 2H), 8.30 (dd, J=7.4, 1.2 Hz, 1H), 8.11 (t, J=5.6 Hz, 1H), 7.92 (d,J=7.6 Hz, 1H), 7.75 (t, J=7.7 Hz, 1H), 7.61 (dd, J=8.3, 1.2 Hz, 1H),7.41 (dt, J=7.7, 1.2 Hz, 1H), 7.22 (dt, J=7.6, 1.2 Hz, 1H), 6.47 (broads, 2H), 4.38 (t, J=7.5 Hz, 2H), 2.86-2.74 (m, 4H), 1.78-1.63 (m, 4H),1.50-1.34 (m, 4H), 0.94 (t, J=7.4 Hz, 3H); MS (E1) m/e 502.2151(502.2151 calcd for C₂₇H₃₀N₆O₂S). Anal calcd for C₂₇H₃₀N₆O₂S: C, 64.52;H, 6.02; N, 16.72. Found: C, 64.03; H, 6.03; N, 16.55.

EXAMPLE 12N-[4-(4-Amino-2-(4-methoxybenzyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl]methanesulfonamide

[0152]

[0153] Methanesulfonic anhydride (0.19 g, 1.1 mmol) was added to astirring solution of1-(4-aminobutyl)-2-(4-methoxybenzyl)-1H-imidazo[4,5-c]quinolin-4-amine(0.4 g, 1.07 mmol), dichloromethane (75 ml) and acetonitrile (100 ml).The reaction was maintained at room temperature for 60 hours. Thesolvent was removed in vacuo and the residue was purified by flashcolumn chromatography (silica gel, 9:1 dichloromethane\methanol). Thefractions containing product were combined, washed with saturatedaqueous sodium bicarbonate, dried (MgSO₄), filtered, and concentrated toprovide 0.3 g ofN-[4-(4-amino-2-(4-methoxybenzyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl]methanesulfonamideas a white solid, m.p. 78.1-79.5° C. ¹H NMR (300 MHz, DMSO-d₆) δ 7.99(d, J=7.6 Hz, 1H), 7.62 (dd, J=8.3, 1.2 Hz, 1H), 7.42 (m, 1H), 7.27-7.21(m, 3H), 6.98 (t, J=5.7 Hz, 1H), 6.89 (d, J=8.7 Hz, 2H), 6.58 (broad s,2H), 4.45 (broad s, 2H), 4.33 (s, 2H), 3.72 (s, 3H), 2.87 (m, 5H), 1.55(broad s, 2H); MS (CI) m/e 454 (M+H).

EXAMPLE 13N¹-[4-(4-Amino-1H-imidazo[4,5-c]quinolin-1-y)butyl]-1-butanesulfonamide

[0154]

[0155] A solution of 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine(9.3 mg, 36 μmol) in 10 mL of dichloromethane in a screw-capped testtube was cooled down to −5° C. Butanesulfonyl chloride (45 μmol) wasadded as a 0.3 M solution in dichloromethane, with argon bubblingthrough the mixture during addition and for an additional 15 seconds.The mixture was allowed to stand at −5° C. overnight. Aminomethylpolystyrene resin (ca. 90 mg, 0.62 meq/g, 100-200 mesh, Bachem) wasadded and the mixture was warmed to reflux and shaken at about 600 rpmfor 3 hours. The mixture was filtered through a Poly-Prep column(Bio-Rad #731-1550) to remove resin. Solvent was removed in vacuo andthe residue was purified by semi-preparative hplc on a Gilson system(Rainin Microsorb C18 column, 21.4×250 mm, 8 micron particle size, 60Apore, 10 mL/min., gradient elution from 2-95% B in 25 min., hold at 95%B for 5 min., where A=0.1% trifluoroacetic acid/water and B=0.1%trifluoroacetic acid/acetonitrile, peak detection at 254 nm fortriggering fraction collection). The semi-prep hplc fractions wereanalyzed by LC-APCI/MS and the appropriate fractions were combined andlyophilized. The solid was dissolved in ca. 3 mL of 2:1dichloromethane-methanol and shaken with ca. 80 mg (300 μmol) ofdiisopropylaminomethyl-polystyrene resin (Argonaut PS-DEA, 3.86 mmol/g)for ˜2 h to liberate the free amine, and then filtered and dried invacuo to give the product as a solid. MS (APCI) m/e 376.16 (M+H).

EXAMPLE 14N¹-{4-[4-Amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl]butyl}-4-fluoro-1-benzenesulfonamide

[0156]

[0157] According to the general method of Example5,1-(4-aminobutyl)-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amineand 4-fluorobenzenesulfonyl chloride were combined. Recrystallizationfrom 4:1 n-propyl acetate\methanol providedN¹-{4-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl]butyl}-4-fluoro-1-benzenesulfonamideas a white crystalline solid, m.p. 191.0-193.0° C. ¹H NMR (300 MHz,DMSO-d₆) δ 7.86-7.81 (m, 2H), 7.67 (broad s, 1H), 7.45-7.39 (m, 2H),5.65 (broad s, 2H), 4.15 (m, 2H), 3.76 (t, J=6.7 Hz, 2H), 3.27 (s, 3H),3.00 (t, J=6.7 Hz, 2H), 2.90 (broad s, 2H), 2.78 (m, 2H), 2.65 (broad s,2H), 1.75 (broad s, 4H), 1.61 (m, 2H), 1.43 (m, 2H); MS (CI) m/e 476(M+H). Analysis: Calculated for C₂₃H₃₀FN₅O₃S: % C, 58.09; % H, 6.36; %N, 14.73; Found: % C, 58.37; % H, 6.35; % N, 14.60.

EXAMPLE 15N-[4-(4-Amino-2-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-4-fluoro-1-benzenesulfonamide

[0158]

[0159] Part A

[0160] A solution of benzoyl chloride (5.3 g, 37.7 mmol) indichloromethane (100 mL) was slowly added to a solution of tert-butylN-{4-[(3-aminoquinolin-4-yl)amino]butyl}carbamate (12.5 g, 37.7 mmol) indichloromethane (250 mL) at ambient temperature. The reaction mixturewas maintained at ambient temperature overnight. The resultingprecipitate was isolated by filtration and dried to provide 11.0 g oftert-butyl N-(4-{[3-(benzoylamino)quinolin-4-yl]amino}butyl)carbamatehydrochloride as a white solid.

[0161] Part B

[0162] Triethylamine (7.26 g, 71.7 mmol) was added to a solution of thematerial from Part A in ethanol (200 mL) and heated at reflux for 2days. The reaction mixture was concentrated to provide an orange syrup.HPLC mass spec analysis showed that the syrup contained the desiredproduct and starting material. The syrup was taken up in dichloromethane(100 mL) and then cooled in an ice bath. Triethylamine (5 mL) andbenzoyl chloride (1.9 mL) were added. The reaction mixture wasmaintained at ambient temperature for 2 days at which time analysis byHPLC indicated that the reaction was not complete. The reaction mixturewas concentrated under vacuum. The residue was taken up in isopropylalcohol (150 mL). Triethylamine (5 mL) was added and the reactionmixture was heated at reflux overnight. The reaction mixture wasconcentrated under vacuum. The residue was purified by flashchromatography (silica gel; eluting with 10% methanol indichloromethane). The fractions containing product were combined andconcentrated under vacuum. The residue was recrystallized fromacetonitrile to provide 6.7 g of tert-butylN-[4-(2-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]carbamate as asolid, m.p. 158-159° C.

[0163] Part C

[0164] 3-Chloroperoxybenzoic acid (1.05 eq of 65%) was slowly added insmall portions to a solution of tert-butylN-[4-(2-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]carbamate (6.56 g,15.75 mmol) in dichloromethane (120 mL). After 3 hours the reaction wasquenched with 1% aqueous sodium bicarbonate (200 mL). The layers wereseparated. The aqueous layer was extracted with dichloromethane (2×50mL). The organic fractions were combined, dried over magnesium sulfateand then concentrated under vacuum to provide a pale orange syrup. Thesyrup was triturated with diethyl ether to provide 6.8 g of1-[4-(tert-butylcarbamyl)butyl]-2-phenyl-1H-imidazo[4,5-c]quinoline-5N-oxideas a pale tan solid, m.p. 178-181° C.

[0165] Part D

[0166] A solution of1-[4-(tert-butylcarbamyl)butyl]-2-phenyl-1H-imidazo[4,5-c]quinoline-5N-oxide(6.8 g, 15.75 mmol) in dichloromethane (100 mL) was chilled in an icebath. Concentrated ammonium hydroxide (30 mL) was added. Tosyl chloride(3.0 g, 15.75 mmol) was added in small portions over a period of 30minutes. The reaction mixture was allowed to warm to ambient temperatureovernight. The reaction was quenched with water (350 mL). The layerswere separated. The aqueous layer was extracted with dichloromethane.The organic fractions were combined, dried over magnesium sulfate andthen concentrated under vacuum to provide a tan solid. This material waspurified by flash chromatography (silica gel eluting with 10% methanolin dichloromethane) to provide 4.8 g of product. The bulk of thematerial was carried on to the next step. A small portion wasrecrystallized from toluene to provide tert-butylN-[4-(4-amino-2-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]carbamate asa solid, m.p. 182-183° C. Analysis: Calculated for C₂₅H₂₉N₅O₂: % C,69.58; % H, 6.77; % N, 16.22; Found: % C, 69.86; % H, 6.95; % N, 15.80.

[0167] Part E

[0168] The material from Part D was dissolved in methanol (15 mL) and 1N hydrochloric acid (100 mL) and then heated at reflux for 2 hours. Thereaction mixture was concentrated under vacuum to a volume of about 50mL. Addition of concentrated ammonium hydroxide to pH 12 did not producea precipitate. The pH was adjusted to 7 with 1 N hydrochloric acid. Themixture was extracted with dichloromethane and then with ethyl acetate.The aqueous layer was concentrated to dryness. The residue was dissolvedin water (50 mL) and then extracted continuously with refluxingchloroform for 36 hours. The chloroform extract was concentrated undervacuum to provide a light tan solid. This material was recrystallizedfrom acetonitrile to provide 2.5 g of1-(4-aminobutyl)-2-phenyl-1H-imidazo[4,5-c]quinolin-4-amine as an offwhite solid, m.p. 175-177° C. Analysis: Calculated for C₂₀H₂₁N₅: % C,72.48; % H, 6.39; % N, 21.13; Found: % C, 72.72; % H, 6.32; % N, 20.71.

[0169] Part F

[0170] 1-(4-Aminobutyl)-2-phenyl-1H-imidazo[4,5-c]quinolin-4-amine(0.331 g, 1.0 mmol) was dissolved in anhydrous acetonitrile (35 mL) andthe solution was cooled to 4° C. A solution of 4-fluorobenzenesulfonylchloride (0.194 g, 1.0 mmol) in anhydrous dichloromethane (10 mL) wasslowly added. The reaction was allowed to slowly warm to ambienttemperature over the weekend. The reaction was quenched by the additionof aqueous saturated sodium bicarbonate solution. The layers wereseparated and the organic layer was concentrated to provide a paleyellow solid. This material was recrystallized from isopropyl alcoholand then further purified by flash chromatography (silica gel elutingwith 10% methanol in dichloromethane). The pure fractions were combinedand concentrated. The residue was recrystallized from isopropyl alcoholto provide 0.2 g ofN-[4-(4-amino-2-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-4-fluoro-1-benzenesulfonamideas a pale yellow solid, m.p. 214-216° C. Analysis: Calculated forC₂₆H₂₄FN₅O₂S: % C, 63.79; % H, 4.94; % N, 14.30; Found: % C, 63.19; % H,4.85; % N, 13.90. Mass spec M+1=490.2

EXAMPLE 16N-[4-(4-Amino-2-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamide

[0171]

[0172] Using the general method of Example 15 Part F,1-(4-aminobutyl)-2-phenyl-1H-imidazo[4,5-c]quinolin-4-amine (0.331 g,1.0 mmol) was reacted with methanesulfonic anhydride to provide 0.14 gofN-[4-(4-Amino-2-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamideas a white solid, m.p. 234-235° C. Mass spec M+1=410.2.

EXAMPLES 17-33

[0173] The compounds shown in the Table below were prepared using thesynthetic method described in Reaction Scheme II above.

[0174] 1-(2-Aminoethyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (25mg) was placed in a 2 dram (7.4 mL) vial. Diisopropylethylamine (11 μL,1.2 eq), dichloromethane (1 mL) and the sulfonyl chloride (1.1 eq) wereadded in order. The vial was placed on a shaker for about 2 hours andthen on a sonicator for about 0.5 hours. The reaction mixture wasallowed to stand at ambient temperature overnight and analyzed by LC/MSto confirm the formation of the desired product. The solvent was removedand the residue was purified by semi-preparative HPLC (Capcell Pak C18column, 35 mm×20 mm, 5 micron particle size, 20 mL/min., gradientelution from 5-95% B in 10 min., hold at 95% B for 2 min., where A=0.1%trifluoroacetic acid/water and B=0.1% trifluoroacetic acid/acetonitrile,peak detection at 254 nm for triggering fraction collection). Thesemi-prep HPLC fractions were analyzed by LC-APCI/MS and the appropriatefractions were combined and lyophilized to provide the trifluoroacetatesalt of the desired sulfonamide. Example # Structure of the Free BaseObserved Mass 17

390.2 18

460.2 19

430.1 20

424.1 21

504.0 22

492.0 23

438.1 24

534.0 25

480.2 26

466.2 27

454.1 28

438.1 29

450.1 30

475.1 31

474.2 32

474.1 33

517.2

EXAMPLE 34N-[2-(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]methanesulfonamideTrifluoroacetate

[0175]

[0176] This compound was prepared using the method of Examples 17-33above except that 1.1 eq of methanesulfonic anhydride was used in placeof the sulfonyl chloride. (Observed Mass=3.62.2)

EXAMPLE 35N-[2-(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]trifluoromethanesulfonamideTrifluoroacetate

[0177]

[0178] This compound was prepared using the method of Examples 17-33above except that 1.1 eq of trifluoromethanesulfonic anhydride was usedin place of the sulfonyl chloride. (Observed Mass=416.1)

EXAMPLES 36-48

[0179] The compounds shown in the Table below were prepared using thesynthetic method described in Reaction Scheme II above.

[0180] 1-(4-Aminobutyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (25mg) was placed in a 2 dram (7.4 mL) vial. Diisopropylethylamine (14 μL,1.0 eq), dichloromethane (1 mL) and the sulfonyl chloride (1.0 eq) wereadded in order. The vial was placed on a shaker for about 30 minutes atwhich time almost everything was in solution. Some time later aprecipitate formed. A small amount of methanol was added and theprecipitate dissolved. The reaction mixture was left on the shaker foran additional hour and then it was put on a sonicator for about 0.5hours. The reaction mixture was analyzed by LC/MS to confirm theformation of the desired product. The solvent was removed and theresidue was purified by semi-preparative HPLC (Capcell Pak C18 column,35 mm×20 mm, 5 micron particle size, 20 mL/min., gradient elution from5-95% B in 10 min., hold at 95% B for 2 min., where A=0.1%trifluoroacetic acid/water and B=0.1% trifluoroacetic acid/acetonitrile,peak detection at 254 nm for triggering fraction collection). Thesemi-prep HPLC fractions were analyzed by LC-APCI/MS and the appropriatefractions were combined and lyophilized to provide the trifluoroacetatesalt of the desired sulfonamide. Example # Structure of Free BaseObserved Mass 36

390.1 37

482.1 38

418.1 39

452.1 40

466.1

EXAMPLES 41-52

[0181] The compounds shown in the Table below were prepared using thesynthetic method described in Reaction Scheme II above.

[0182] 1-(4-Aminobutyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (25mg) was placed in a 2 dram (7.4 mL) vial. Diisopropylethylamine (14 μL,1.0 eq), dichloromethane (1 mL) and the sulfonyl chloride (1.0 eq) wereadded in order. The vial was placed on a sonicator at ambienttemperature for about 60 minutes. The reaction mixture was analyzed byLC/MS to confirm the formation of the desired product. The solvent wasremoved and the residue was purified by semi-preparative HPLC (CapcellPak C18 column, 35 mm×20 mm, 5 micron particle size, 20 mL/min.,gradient elution from 5-95% B in 10 min., hold at 95% B for 2 min.,where A=0.1% trifluoroacetic acid/water and B=0.1% trifluoroaceticacid/acetonitrile, peak detection at 254 nm for triggering fractioncollection). The semi-prep HPLC fractions were analyzed by LC-APCI/MSand the appropriate fractions were combined and lyophilized to providethe trifluoroacetate salt of the desired sulfonamide. Example #Structure of Free Base Observed Mass 41

502.1 42

502.1 43

503.2 44

458.1 45

494.2 46

578.2 47

508.3 48

520.1 49

466.2 50

478.2 51

418.2 52

560.1

EXAMPLE 53N-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]trifluoromethanesulfonamideTrifluoroacetate

[0183]

[0184] This compound was prepared using the method of Examples 41-52above except that 1.0 eq of trifluoromethanesulfonic anhydride was usedin place of the sulfonyl chloride. (Observed Mass=444.1)

EXAMPLES 54-71

[0185] The compounds shown in the Table below were prepared using thesynthetic method described in Reaction Scheme IV above.

[0186] Part A

[0187] A catalytic amount of platinum (IV) oxide was added to a solutionof 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (2.75 g, 10.8mmol) in trifluoroacetic acid (150 mL). The reaction mixture was placedunder a hydrogen atmosphere at 50 psi (3.44×10⁵ Pa). After 1 weekanalysis by mass spectroscopy indicated the presence of both startingmaterial and the tetrahydro product. Fresh catalyst was added to thereaction mixture and hydrogenation was continued at 50 psi (3.44×10⁵Pa). After 2 weeks the reaction mixture was filtered to remove thecatalyst. The filtrate was concentrated under vacuum. The residue wasdissolved in 1N hydrochloric acid (120 mL) and the solution was stirredat ambient temperature for 1 hour. The solution was made basic (pH 10)by the addition of 50% sodium hydroxide and then extracted withdichloromethane (5×100 mL). The extracts were combined and concentratedunder vacuum to provide 2.08 g of1-(4-aminobutyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine asa white solid.

[0188] Part B

[0189]1-(4-Aminobutyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine(25 mg) was placed in a 2 dram (7.4 mL) vial. Diisopropylethylamine (11μL, 1.2 eq), dichloromethane (1 mL) and the sulfonyl chloride (1.1 eq)were added in order. The vial was placed on a shaker for about 6 hours.The reaction mixture was allowed to stand at ambient temperatureovernight and was analyzed by LC/MS to confirm the formation of thedesired product. The solvent was removed and the residue was purified bysemi-preparative HPLC (Capcell Pak C18 column, 35 mm×20 mm, 5 micronparticle size, 20 mL/min., gradient elution from 5-95% B in 10 min.,hold at 95% B for 2 min., where A=0.1% trifluoroacetic acid/water andB=0.1% trifluoroacetic acid/acetonitrile, peak detection at 254 nm fortriggering fraction collection). The semi-prep HPLC fractions wereanalyzed by LC-APCI/MS and the appropriate fractions were combined andlyophilized to provide the trifluoroacetate salt of the desiredsulfonamide. Example # Structure of Free Base Observed Mass 54

366.2 55

366.1 56

436.2 57

406.1 58

400.1 59

434.0 60

468.0 61

526.0 62

456.1 63

442 64

414 65

430 66

508.0 67

414.1 68

426.1 69

451.1 70

450.1 71

493.1

EXAMPLE 72N-[4-(4-Amino-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamideTrifluoroacetate

[0190]

[0191] This compound was prepared using the method of Examples 54-71above except that 1.1 eq of methanesulfonic anhydride was used in placeof the sulfonyl chloride. (Observed Mass=338.2)

EXAMPLES 73-201

[0192] The compounds in the table below were prepared according thesynthetic method of Reaction Scheme II above using the following generalmethod.

[0193] The 1H-imidazo[4,5-c]quinolin-4-amine (50 mg) was placed in a 2dram (7.4 mL) vial. Diisopropylethylamine (1.2 eq) in dichloromethane(˜1 mL) was added. A solution containing the sulfonyl chloride (1.1 eq)in dichloromethane (˜1 mL) was added. The vial was placed on a shakerfor about 2-16 (usually 2) hours at ambient temperature. The reactionmixture was analyzed by LC/MS to confirm the formation of the desiredproduct. The solvent was removed and the residue was purified bysemi-preparative HPLC (Capcell Pak C18 column, 35 mm×20 mm, 5 micronparticle size, 20 mL/min., gradient elution from 5-95% B in 10 min.,hold at 95% B for 2 min., where A=0.1% trifluoroacetic acid/water andB=0.1% trifluoroacetic acid/acetonitrile, peak detection at 254 nm fortriggering fraction collection). The semi-prep HPLC fractions wereanalyzed by LC-APCI/MS and the appropriate fractions were combined andlyophilized to provide the trifluoroacetate salt of the desiredsulfonamide. Example # Structure of the Free Base APCI-MS m/e 73

526.2 74

432.2 75

600.3 76

578.2 77

530.1 78

530, 532.0 79

565.0 80

520.1 81

512.1 82

452.1 83

497.1 84

496.1 85

536.1 86

531.0, 533.0 87

470.1 88

497.1 89

526.2 90

542.0 91

536.1 92

520.0, 522.0 93

488.1 94

471.1 95

470.1 96

528.1 97

511.1 98

508.1 99

537.9 100

516.0, 518.0 101

492.0, 494.0 102

603.1 103

520.1 104

482.1 105

560.0, 562 106

484.1 107

522.1 108

364.1 109

432.0 110

519.1 111

392.2 112

460.1 113

468.2 114

547.3 115

406.1 116

420.1 117

434.1 118

454.1 119

468.1 120

472.1 121

472.1 122

472.1 123

473.1 124

484.1 125

484.1 126

488.1 127

488.1 128

488.0 129

490.1 130

490.1 131

494.0 132

496.2 133

496.1 134

496.2 135

499.1 136

499.1 137

508.1 138

513.1 139

514.1 140

514.1 141

518.0 142

522.1 143

522.0, 524.0 144

522.0, 524.0 145

522.0, 524.0 146

522.0, 524.0 147

522.0, 524.0 148

528.2 149

528.0, 530.0 150

528.0, 530.0 151

532, 534.0 152

532, 534.0 153

538.1 154

538.1 155

538, 540.0 156

580.0 157

605.1 158

454.2 159

468.2 160

479.2 161

532.2 162

479.1 163

486.1 164

490.2 165

498.1 166

498.1 167

502.1 168

502.1 169

504.2 170

504.1 171

505.2 172

506.1 173

506.2 174

506.2 175

510.3 176

510.2 177

513.2 178

513.2 179

513.2 180

524.2 181

526.2 182

530.2 183

532.2 184

534.1 185

533.1 186

536.1, 538.1 187

544.1 188

546.3 189

556, 558.1 190

556, 558.1 191

556, 558.1 192

562, 564.1 193

567.2 194

580.3 195

593.2 196

606.0, 608.0, 609.9 197

610.0, 612.0, 614.0 198

616, 618.1 199

616.0, 617.9, 620.0 200

528.3 201

522.2

EXAMPLES 202-213

[0194] The examples in the table below were prepared according to thesynthetic method of Reaction Scheme VI above.

[0195] Part A

[0196] The tetrahydroquinoline amine starting materials were prepared asfollows.

[0197] A catalytic amount of platinum (IV) oxide was added to a solutionof 1-(4-aminobutyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (2.2 g,7.06 mmol) in trifluoroacetic acid (200 mL). The reaction mixture washydrogenated at 50 psi (3.44×10⁵ Pa) on a Parr apparatus for 6 days. Thereaction mixture was filtered to remove the catalyst and the filtratewas concentrated under vacuum. The residue was combined with 1 Nhydrochloric acid (100 mL) and heated on a steam bath for 2 hours. Themixture was cooled, made basic with ammonium hydroxide and thenextracted with dichloromethane. The extract was concentrated undervacuum to provide of1-(4-aminobutyl)-2-butyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amineas a solid, m.p. 63-67° C.

[0198] A catalytic amount of platinum (IV) oxide was added to a solutionof 1-(4-aminobutyl)-2-methoxyethyl-1H-imidazo[4,5-c]quinolin-4-amine(7.7 g, 24.5 mmol) in trifluoroacetic acid (250 mL). The reactionmixture was hydrogenated at 50 psi (3.44×10⁵ Pa) on a Parr apparatus.The progress of the reaction was monitored by LC/MS. Additional catalystwas added 7, 11, and 17 days after the start of the reaction. After 25days the reaction was complete. The reaction mixture was filteredthrough a layer of Celite® filter aid to remove the catalyst and thefiltrate was concentrated under vacuum. The residue was combined with 1N hydrochloric acid (100 mL) and stirred overnight. The mixture was madebasic (pH=11) with ammonium hydroxide and then extracted withdichloromethane (3×300 mL). The extracts were combined and concentratedunder vacuum to provide 3.5 g of1-(4-aminobutyl)-6,7,8,9-tetrahydro-2-methoxyethyl-1H-imidazo[4,5-c]quinolin-4-amineas a solid.

[0199] Part B

[0200] The tetrahydroimidazoquinoline amines from Part A were reactedwith the appropriate sulfonyl chloride using the method of Examples73-201 above to provide the desired sulfonamide. Example # Structure ofthe Free Base APCI-MS m/e 202

394.20 203

422.1 204

462.1 205

470.1 206

549.2 207

410.2 208

424.2 209

438.2 210

458.1 211

472.2 212

532.2 213

551.2

EXAMPLE 214N-[4-(4-Amino-6,7,8,9-tetrahydro-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamideTrifluoroacetate

[0201]

[0202] This compound was prepare using the method of Examples 202-213above except that methanesulfonic anhydride was used in place of thesulfonyl chloride.

EXAMPLE 215

[0203]N-[4-(4-Amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N-methyl-3,5-dimethylisooxazolo-4-sulfonamideTrifluoroacetate

[0204] Part A

[0205] Using the general method of Example DC001,1-(4-aminobutyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-aminewas reacted with 3,5-dimethyloxazole-4-sulfonyl chloride to provideN-[4-(4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-3,5-dimethylisooxazolo-4-sulfonamidetrifluoroacetate.

[0206] Part B

[0207] Sodium hydride (5.8 mg) was added to a solution of the materialfrom Part A (25.4 mg) in dimethylformamide. Iodomethane (3.2 μL) wasadded and the reaction mixture was shaken at ambient temperature for 2hours. The reaction mixture was analyzed by LC/MS to confirm theformation of the desired product. The solvent was removed and theresidue was purified by semi-preparative HPLC (Capcell Pak C18 column,35 mm×20 mm, 5 micron particle size, 20 mL/min., gradient elution from5-95% B in 10 min., hold at 95% B for 2 min., where A=0.1%trifluoroacetic acid/water and B=0.1% trifluoroacetic acid/acetonitrile,peak detection at 254 nm for triggering fraction collection). Thesemi-prep HPLC fractions were analyzed by LC-APCI/MS and the appropriatefractions were combined and lyophilized. The lyophilized material waspurified a second time by semi-preparative HPLC using the sameconditions except that the gradient elution from 5-95% B was run for 60minutes instead of 10 minutes. The semi-prep HPLC fractions wereanalyzed by LC-APCI/MS and the appropriate fractions were combined andlyophilized to provide the trifluoroacetate salt of the desired amide.

EXAMPLE 216N-[4-(4-Amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N-methyltrifluoromethanesulfonamideTrifluoroacetate

[0208]

[0209] This compound was prepared using the general method of Example215 above, except that trifluoromethanesulfonic anhydride was used inplace of the sulfonyl chloride in Part A.

EXAMPLES 217-221

[0210] The examples in the table below were prepare using the followinggeneral method. The 1H-imidazo[4,5-c]quinolin-4-amine or the6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine (50 mg) was placedin a 2 dram (7.4 mL) vial. Dichloromethane (2 mL) anddiisopropylethylamine (1.2 eq) were added. Dimethylsulfamoyl chloride(1.1 eq) was added. The vial was placed on a shaker for about 2-4 hoursat ambient temperature. The reaction mixture was analyzed by LC/MS toconfirm the formation of the desired product. The solvent was removedand the residue was purified by semi-preparative HPLC (Capcell Pak C18column, 35 mm×20 mm, 5 micron particle size, 20 mL/min., gradientelution from 5-95% B in 10 min., hold at 95% B for 2 min., where A=0.1%trifluoroacetic acid/water and B=0.1% trifluoroacetic acid/acetonitrile,peak detection at 254 nm for triggering fraction collection). Thesemi-prep HPLC fractions were analyzed by LC-APCI/MS and the appropriatefractions were combined and lyophilized to provide the trifluoroacetatesalt of the desired sulfamide. Ex- am- APCI-MS ple # Structure of theFree Base m/e 217

393.1 218

421.2 219

483.3 220

423.2 221

425.1

EXAMPLES 222-228

[0211] The examples in the table below were prepared according to thesynthetic method shown in Reaction Scheme V above.

[0212]1-(4-Aminobutyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine(50 mg) was placed in a 2 dram (7.4 mL) vial. 4-(Dimethylamino)pyridine(19 mg, 1.0 eq) and dichloromethane (800 μL) were added. The vial wassealed and cooled to −78° C. in a dry ice/acetone bath. Sulfurylchloride (186 μL of 1 M in dichloromethane) was added. The vial was puton a shaker for about 30 minutes and then cooled back down to −78° C. Aseparate vial was charged with the amine of formula R₄R₅NH (2.0 eq),triethylamine (2.0 eq) and dichloromethane (1 mL) and cooled to −78° C.The amine/triethylamine solution was added to the first vial. The vialwas placed on a shaker at ambient temperature for about 1 hour. Thereaction mixture was analyzed by LC/MS to confirm the formation of thedesired product. The solvent was removed and the residue was purified bysemi-preparative HPLC (Capcell Pak C18 column, 35 mm×20 mm, 5 micronparticle size, 20 mL/min., gradient elution from 5-95% B in 10 min.,hold at 95% B for 2 min., where A=0.1% trifluoro acetic acid/water andB=0.1% trifluoroacetic acid/acetonitrile, peak detection at 254 nm fortriggering fraction collection). The semi-prep HPLC fractions wereanalyzed by LC-APCI/M:S and the appropriate fractions were combined andlyophilized to provide the trifluoroacetate salt of the desiredsulfamide. Ex- am- APCI-MS ple # Structure of the Free Base m/e 222

449.2 223

475.3 224

469.1 225

490.2 226

497.1 227

533.2 228

479.1

EXAMPLES 229-231

[0213] The examples in the table below were prepared using the method ofExamples 222-228 above except that the amine of formula R₄R₅NH wasreacted with the sulfuryl chloride to provide the sulfamoyl chlorideintermediate which was then reacted with 2.0 eq of1-(4-aminobutyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine.Ex- APCI-MS ample # Structure of the Free Base m/e 229

447.1 230

449.2 231

483.2

EXAMPLE 232N-[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]benzenesulfonamide

[0214]

[0215] Triethylamine (1.18 mL, 8.5 mmol) was added to a mixture of1-(4-aminobutyl)-2-ethyl-1H-imidazo[4,5-c]quinolin-4-amine (2.00 g, 7.1mmol) and chloroform (200 mL). The resulting solution was chilled in anacetone/ice bath for 10 minutes. Benzenesulfonyl chloride (0.90 mL, 8.5mmol) was slowly added over a period of 5 minutes. After 45 minutes 0.2equivalents of triethylamine was added. After 6 hours the reactionmixture was washed with brine (2×250 mL) and with water (1×100 mL),dried over magnesium sulfate and then concentrated under reducedpressure. The residue was recrystallized from N,N-dimethylformamide. Therecrystallized material and the filtrate were both slurried withmethanol. The resulting solids were isolated by filtration, combined,and then dried in an Abderhalden drying apparatus overnight to provide0.80 g ofN-[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]benzenesulfonamideas a white solid, m.p. 180.6-182.0° C. Analysis: Calculated forC₂₂H₂₅N₅O₂S 0.25H₂O: % C, 61.73; % H, 6.00; % N, 16.36; Found: % C,61.79; % H, 6.04; % N, 16.43.

EXAMPLE 233N-[4-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]benzenesulfonamide

[0216]

[0217] Part A

[0218] Tert-butyl4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butylcarbamate (5.00 g, 13.1mmol) was combined with hydrochloric acid (50 mL of 4.0 M in dioxane)and stirred for 1.5 hours. The reaction mixture was diluted withdichloromethane (˜200 mL). Saturated sodium bicarbonate solution wasadded until a pH of 8 was obtained. A precipitate formed in the aqueousphase. The layers were separated. The precipitate in the aqueous layerwas isolated by filtration, slurried with water and then isolated byfiltration to provide 3.6 g of4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butan-1-amine.

[0219] Part B

[0220] The material from Part A was combined with chloroform (600 mL)and warmed to 40° C. Triethylamine (3.48 mL, 25 mmol) was added and asolution was obtained. Benzenesulfonyl chloride (1.60 mL, 12.5 mmol) wasadded. The reaction mixture was stirred at 40° C. overnight. Thereaction mixture was cooled to ambient temperature and then concentratedunder reduced pressure. The residue was taken up in dichloromethane(˜100 mL), washed with water (3×125 mL), dried over magnesium sulfateand then concentrated under reduced pressure to provide 3.96 g ofN-[4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]benzenesulfonamideas a yellow crystalline solid, m.p. 155.9-157.1° C.

[0221] Part C

[0222] 3-Chloroperoxybenzoic acid (896 mg of 77%) was added over aperiod of 5 minutes to a solution ofN-[4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]benzenesulfonamide(1.0 g, 2.4 mmol) in chloroform (100 mL). After 2.5 hours an additional0.1 equivalent of 3-chloroperoxybenzoic acid was added. After 3 hoursthe reaction was stored at a reduced temperature overnight. The reactionmixture was washed with saturated sodium bicarbonate solution (3×150 mL)and then concentrated under reduced pressure to provide 1.44 g of crudeproduct. This material was recrystallized from methyl acetate to provide0.67 g of1-{4-[(phenylsulfonyl)amino]butyl}-2-propyl-1H-imidazo[4,5-c]quinolin-5N-oxideas a brown solid, m.p. 203.8-205.2° C.

[0223] Part D

[0224] Ammonium hydroxide (3.5 mL of 27%) was added to a mixture of thematerial from Part C and dichloromethane (15 mL). After 10 minutes tosylchloride (0.35 g) was slowly added over a period of 5 minutes. After 45minutes the reaction mixture was stored at a reduced temperature overthe weekend. An additional 35 mg of tosyl chloride was added and thereaction mixture was stirred for 1 hour. The organic phase was separatedand then washed with saturated sodium bicarbonate solution (3×80 mL). Aprecipitate formed in the aqueous phase. This material was isolated byfiltration and then recrystallized from methyl acetate. The resultingsolid and the filtrate were combined, dissolved in dichloromethanecontaining a small amount of methanol, and then purified by columnchromatography (silica gel eluting with 10% methanol indichloromethane). The resulting material was purified by columnchromatography (silica gel eluting with 0-7.5% methanol indichloromethane). This material was recrystallized 3 times from methylacetate to provide 42 mg ofN-[4-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]benzenesulfonamideas a white solid, m.p. 158.8-160.8° C. Analysis: Calculated forC₂₃H₂₇N₅O₂S 0.25 C₃H₆O₂: % C, 62.15; % H, 6.22; % N, 15.59; Found: % C,62.41; % H, 5.91; % N, 15.41.

EXAMPLE 234N-[4-(4-amino-2-hexyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]benzenesulfonamide

[0225]

[0226] Part A

[0227] Using the general method of Example 233 Part A, tert-butyl4-(2-hexyl-1H-imidazo[4,5-c]quinolin-1-yl)butylcarbamate (33.85 g) washydrolyzed to provide 3.43 g of4-(2-hexyl-1H-imidazo[4,5-c]quinolin-1-yl)butan-1-amine as an off whitesolid, m.p. 172.2-174.2° C.

[0228] Part B

[0229] Using the general method of Example 233 Part B except that thereaction was run at ambient temperature,4-(2-hexyl-1H-imidazo[4,5-c]quinolin-1-yl)butan-1-amine (1.20 g, 3.7mmol) was reacted with benzenesulfonyl chloride (429 μL, 3.7 mmol) toprovide 0.75 g ofN-[4-(2-hexyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]benzenesulfonamide asa light yellow solid, m.p. 137.0-138.1° C.

[0230] Part C

[0231] Using the general method of Example 233 Part C,N-[4-(2-hexyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]benzenesulfonamide(0.95 g, 2.0 mmol) was oxidized to provide 1.21 g of crude1-{4-[(phenylsulfonyl)amino]butyl}-2-hexyl-1H-imidazo[4,5-c]quinolin-5N-oxide.

[0232] Part D

[0233] Using the general method of Example 233 Part D, the material fromPart C was aminated to provide 118 mg ofN-[4-(4-amino-2-hexyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]benzenesulfonamideas an off white crystalline solid, m.p. 84.8-85.4° C. Analysis:

[0234] Calculated for C₂₆H₃₃N₅O₂S 0.5H₂O: % C, 63.91; % H, 7.01; % N,14.33; Found: % C, 63.63; % H, 6.93; % N, 14.80.

EXAMPLE 235N-[4-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamide

[0235]

[0236] Part A

[0237] Using the general method of Example 233 Part B except that thereaction was run at ambient temperature,4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butan-1-amine (2.00 g, 7.1mmol) was reacted with methanesulfonyl chloride (1.65 mL, 21.3 mmol) toprovide 1.23 g ofN-[4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamideas a light yellow solid, m.p. 133.2-134.6° C.

[0238] Part B

[0239] Using the general method of Example 233 Part C,N-[4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamidewas oxidized to provide 1.44 g of crude1-{4-[(methylsulfonyl)amino]butyl}-2-propyl-1H-imidazo[4,5-c]quinolin-5N-oxideas a light yellow solid.

[0240] Part C

[0241] Using the general method of Example 233 Part D, the material fromPart B was aminated to provide 0.21 g ofN-[4-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamideas an off white crystalline solid, m.p. 186.5-187.9° C. Analysis:Calculated for C₁₈H₂₅N₅O₂S 0.25H₂O: % C, 56.89; % H, 6.76; % N, 18.43;Found: % C, 56.95; % H, 6.89; % N, 18.13.

EXAMPLE 236N-[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamide

[0242]

[0243] Part A

[0244] Using the general method of Example 233 Part A, tert-butyl4-(2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butylcarbamate (20.69 g) washydrolyzed to provide 14.94 g of4-(2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butan-1-amine as an off whitesolid, m.p. 84.8-88.7° C.

[0245] Part B

[0246] Using the general method of Example 233 Part B,4-(2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butan-1-amine (4.00 g, 14.9mmol) was reacted with methanesulfonyl chloride to provide 1.78 g ofN-[4-(2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamide asa light yellow solid.

[0247] Part C

[0248] Using the general method of Example 233 Part C, the material fromPart B was oxidized to provide ˜2.00 g of crude1-{4-[(methylsulfonyl)amino]butyl}-2-ethyl-1H-imidazo[4,5-c]quinolin-5N-oxide.

[0249] Part D

[0250] Using the general method of Example 233 Part D, the material fromPart C was aminated to provide 0.42 g ofN-[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamideas a white solid, m.p. 203.3-204.4° C. Analysis: Calculated forC₁₇H₂₃N₅O₂S: % C, 56.49; % H, 6.41; % N, 19.37; Found: % C, 56.21; % H.6.36; % N, 19.09.

EXAMPLE 237N-[4-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]benzenesulfonamide

[0251]

[0252] Using the general method of Example 232,1-(4-aminobutyl)-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (0.50 g, 1.9mmol) was reacted with benzenesulfonyl chloride (0.24 mL, 1.9 mmol) toprovide 0.38 g ofN-[4-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]benzenesulfonamideas brown granules, m.p. 215.4-216.0° C. Analysis: Calculated forC₂₁H₂₃N₅O₂S: % C, 61.59; % H, 5.66; % N, 17.10; Found: % C, 61.24; % H,5.65; % N, 16.95.

EXAMPLE 238N-[4-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamide

[0253]

[0254] Using the general method of Example 232,1-(4-aminobutyl)-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (1.00 g, 3.7mmol) was reacted with methanesulfonyl chloride (0.46 mL, 5.9 mmol) toprovide 0.16 g ofN-[4-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamideas an off white solid, m.p. 229.4-230.5° C. Analysis: Calculated forC₁₆H₂₁N₅O₂S 0.25H₂O: % C, 54.60; % H, 6.16; % N, 19.90; Found: % C,54.80; % H, 6.24; % N, 19.58.

EXAMPLE 239N-[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]methanesulfonamide

[0255]

[0256] Part A

[0257] Tert-butyl3-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propylcarbamate (˜80 g) wasdissolved in 1,4-dioxane (400 mL) with gentle heating. Hydrochloric acid(55 mL of 4.0 M in 1,4-dioxane) was added in a single portion and thereaction was heated to reflux. The reaction was monitored by HPLC.Additional acid (150-200 mL) was added and the reaction mixture wasrefluxed until the reaction was complete. The reaction mixture wascooled to ambient temperature. A solid was isolated by filtration togive ˜72 g of 3-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propylaminehydrochloride. This material was combined with that from a previousexperiment and then dissolved in water (400 mL). The solution wasneutralized with solid potassium carbonate. At pH 7 a solidprecipitated. The solid was isolated by filtration and then dissolved inwater (1500 mL). The pH was adjusted to pH 10 with solid potassiumcarbonate. The solution was extracted with chloroform until HPLCanalysis showed that no amine remained in the aqueous layer. The organiclayers were combined and then concentrated under reduced pressure toprovide 45 g of 3-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propylamine.

[0258] Part B

[0259] Triethylamine (1.1 g, 10.6 mmol) was added with stirring to asolution of 3-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propylamine (2.00g, 7.08 mmol) in dichloromethane (˜150 mL). Methanesulfonyl chloride(892 mg, 7.79 mmol) was added and the reaction was stirred undernitrogen overnight. The reaction mixture was washed with aqueous 1%sodium bicarbonate solution (3×50 mL). The aqueous washes were extractedwith dichloromethane (2×20 mL). The organics were combined, dried overmagnesium sulfate and then concentrated under reduced pressure toprovide 1.89 g ofN-[3-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]methanesulfonamideas a light brown solid.

[0260] Part C

[0261] Using the general method of Example 233 Part C, the material fromPart B was oxidized to provide 1.24 g ofN-[3-(2-butyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)propyl]methanesulfonamide.

[0262] Part D

[0263] Using the general method of Example 233 Part D, the material fromPart C was animated to provide 690 mg ofN-[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]methanesulfonamideas a light tan solid, m.p. 239.2-240.8° C. Analysis: Calculated forC₁₈H₂₅N₅O₂S: % C, 57.58; % H, 6.71; % N, 18.65; Found: % C, 57.37; % H,6.78; % N, 18.42.

EXAMPLE 240N-[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]benzenesulfonamide

[0264]

[0265] Part A

[0266] Using the general method of Example 239 Part B,3-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propylamine (2.00 g, 7.08mmol) was reacted with benzenesulfonyl chloride (1.38 g, 7.79 mmol) toprovide 2.83 g ofN-[3-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]benzenesulfonamideas a light red foam.

[0267] Part B

[0268] Using the general method of Example 233 Part C, the material fromPart A was oxidized to provide 3.28 g ofN-[3-(2-butyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)propyl]benzenesulfonamide.

[0269] Part C

[0270] Using the general method of Example 233 Part D, the material fromPart B was animated to provide 1.08 g ofN-[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]benzenesulfonamideas a light tan solid, m.p. 210.5-212.0° C. Analysis: Calculated forC₂₃H₂₇N₅O₂S: % C, 63.13; % H. 6.22; % N, 16.01; Found: % C, 62.89; % H,6.16; % N, 15.74.

EXAMPLE 241N-[4-(4-amino-2-hexyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamide

[0271]

[0272] Part A

[0273] Using the general method of Example 232,4-(2-hexyl-1H-imidazo[4,5-c]quinolin-1-yl)butan-1-amine (1.00 g, 3.1mmol) was reacted with methanesulfonyl choride (0.48 mL, 6.2 mmol) toprovide 1.15 g ofN-[4-(2-hexyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamide asa white solid.

[0274] Part B

[0275] Using the general method of Example 233 Part C,N-[4-(2-hexyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamide(1.47 g, 3.7 mmol) was oxidized to provide 3.78 g of crude1-{4-[(methylsulfonyl)amino]butyl}-2-hexyl-1H-imidazo[4,5-c]quinolin-5N-oxideas a yellow residue.

[0276] Part C

[0277] Using the general method of Example 233 Part D, the material fromPart B was animated to provide 0.28 g ofN-[4-(4-amino-2-hexyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamideas an off white solid, m.p. 170.2-171.1° C. Analysis: Calculated forC₂₁H₃₁N₅O₂S: % C, 60.40; % H, 7.48; % N, 16.77; Found: % C, 59.97; % H,7.26; % N, 16.33.

EXAMPLE 242N-{8-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]octyl}benzenesulfonamide

[0278]

[0279] Under a nitrogen atmosphere a solution of1-(8-aminooctyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine(1.0 g, 2.7 mmol) in dichloromethane (50 mL) was cooled to 0° C.Triethylamine (415 μL, 2.98 mmol) was added followed by benzenesulfonylchloride (345 μL, 2.71 mmol). The reaction mixture was allowed to warmslowly to ambient temperature and then it was maintained overnight. Thereaction mixture was washed with water, dried over magnesium sulfate andthen concentrated under reduced pressure. The residue was purified bycolumn chromatography (50 g of silica gel eluting with 7.5% methanol indichloromethane). The purified material was recrystallized from propylacetate, triturated with hexanes, and then dried in a vacuum oven toprovide 590 mg ofN-{8-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]octyl}benzenesulfonamideas a yellow powder, m.p. 146-149° C. Analysis: Calculated forC₂₇H₃₅N₅O₃S: % C, 63.63; % H, 6.92; % N, 13.74; Found: % C, 62.96; % H,7.03; % N, 13.09. Karl Fisher showed 0.16% or 0.045 mole water.

[0280]¹H NMR (300 MHz, DMSO-d₆) δ 801 (d, J=7.8 Hz, 1H), 7.78 (m, 2H),7.65-7.55 (m, 5H), 7.45 (m, 1H), 7.28 (m, 1H), 6.71 (s, 2H), 4.50 (m,2H), 3.83 (m, 2H), 3.5 (broad s, 3H), 3.18 (m, 2H), 2.71 (m, 2H), 1.77(m, 2H), 1.38-1.17 (m, 10H);

[0281]¹³C NMR (75 MHz, DMSO-d₆) 151.7, 151.3, 144.0, 141.0, 132.8,132.6, 129.5, 127.0, 126.8, 125.9, 121.9, 120.4, 114.9, 70.5, 58.5,45.3, 42.8, 30.0, 29.2, 28.8, 28.7, 27.5, 26.2, 26.1;

[0282] MS m/z 510 (M+H).

EXAMPLE 243N-{8-[4-amino-2-(2-methoxyethyl)-H-imidazo[4,5-c]quinolin-1-yl]octyl}methanesulfonamide

[0283]

[0284] Using the general method of Example 242,1-(8-aminooctyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine(800 mg, 2.17 mmol) was reacted with methanesulfonyl chloride (172 μL,2.17 mmol) to provide 720 mg ofN-{8-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]octyl}methanesulfonamideas a yellow powder, m.p. 109-110° C. Analysis: Calculated forC₂₂H₃₃N₅O₃S: % C, 59.04; % H, 7.43; % N, 15.65; Found: % C, 58.78; % H,7.38; % N, 15.48.

[0285]¹H NMR (300 MHz, DMSO-d₆) δ 8.01 (d, J=8.3 Hz, 1H), 7.62 (d, J=8.3Hz, 1H), 7.42 (m, 1H), 7.26 (m, 1H), 6.91 (m, 1H), 6.51 (s, 2H), 4.51(t, J=7.3 Hz, 2H), 3.83 (t, J=6.8 Hz, 2H), 3.34 (s, 3H), 3.18 (t, J=6.8Hz, 2H), 2.89 (m, 2H), 2.86 (s, 3H), 1.80 (m, 2H), 1.27 (m, 10H);

[0286]¹³C NMR (125 MHz, DMSO-d₆) 152.0, 151.0, 145.0, 132.6, 132.6,126.7, 126.6, 121.56, 120.3, 115.1, 70.5, 58.5, 45.3, 42.8, 30.0, 29.7,28.9, 28.8, 27.5, 26.4, 26.2; MS m/z 448 (M+1).

EXAMPLE 244N-[8-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)octyl]methanesulfonamide

[0287]

[0288] Using the general method of Example 242,1-(8-aminooctyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (1.2 g, 3.26mmol) was reacted with methanesulfonyl chloride (260 μL, 3.26 mmol) toprovide 0.70 g ofN-[8-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)octyl]methanesulfonamideas a tan powder, m.p. 121-124° C. Analysis: Calculated for C₂₃H₃₅N₅O₃S:% C, 61.99: % H, 7.92; % N, 15.72; Found: % C, 62.01; % H, 7.97; % N,15.75.

[0289]¹H NMR (300 MHz, DMSO-d₆) δ 8.01 (d, J=8.3 Hz, 1H), 7.61 (dd,J=8.3, 1.0 Hz, 1H), 7.41 (dt, J=8.31.5 Hz, 1H), 7.25 (dt, J=8.3, 1.5 Hz,1H), 6.91 (t, J=4.9 Hz, 1H), 6.47 (s, 2H), 4.48 (t, J=7.3 Hz, 2H), 2.90(m, 4H), 2.86 (s, 3H), 1.80 (m, 4H), 1.44 (m, 6H), 1.27 (m, 6H), 0.96(t, J=7.3 Hz, 3H);

[0290]¹³C NMR (500 MHz, DMSO-d₆) 153.3, 152.1, 145.1, 132.5, 126.8,126.7, 126.6, 121.5, 120.2, 115.2, 45.1, 42.8, 39.6, 30.1, 30.0, 29.8,28.9, 28.8, 26.5, 26.4, 26.2, 22.3, 14.1;

[0291] MS m/z 446 (M+1).

EXAMPLE 245N-[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]-5-(dimethylamino)naphthalene-1-sulfonamide

[0292]

[0293] Under a nitrogen atmosphere triethylamine (765 mg, 7.56 mmol) wasadded to a solution of1-(3-aminopropyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (1.5 g, 5.04mmol) in 1-methyl-2-pyrrolidinone (75 mL). A solution of5-dimethylamino-1-naphthalenesulfonyl chloride (1.5 g, 5.55 mmol) in1-methyl-2-pyrrolidinone was added. The reaction was monitored by HPLC.The reaction mixture was combined with water (500 mL) and the pH wasadjusted to 10 with solid potassium carbonate. The resulting yellowprecipitate was isolated by filtration, rinsed with water and thenpurified by column chromatography (silica gel eluting with 1-5% methanolin chloroform). The purified material was recrystallized fromacetonitrile to provide 1.76 g ofN-[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]-5-(dimethylamino)naphthalene-1-sulfonamideas a solid, m.p. 216.5-217.5° C. Analysis: Calculated for C₂₉H₃₄N₆O₂S: %C, 65.64; % H, 6.46; % N, 15.84; Found: % C, 65.52; % H, 6.44; % N,15.90.

EXAMPLE 246N-[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]-4-methylbenzenesulfonamide

[0294]

[0295] Using the general method of Example 2451-(3-aminopropyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (1.5 g, 5.04mmol) was reacted with p-toluenesulfonyl chloride (1.08 g, 5.55 mmol) toprovide 1.57 g ofN-[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]-4-methylbenzenesulfonamideas an off white powder, m.p. 197.0-198.5° C. Analysis: Calculated forC₂₄H₂₉N₅O₂S: % C, 63.83; % H, 6.47; % N, 15.51; Found: % C, 63.68; % H,6.40; % N, 15.51.

EXAMPLE 247N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}methanesulfonamide

[0296]

[0297] Using the general method of Example 242,1-(3-aminopropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine(1.53 g, 5.11 mmol) was reacted with methanesulfonyl chloride to provide800 mg ofN-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}methanesulfonamideas light yellow needles, m.p. 193-194° C. Analysis: Calculated forC₁₇H₂₃N₅O₃S: % C, 54.09; % H, 6.14; % N, 18.55; Found: % C, 54.09; % H,5.93; % N, 18.49.

EXAMPLE 248N-[8-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)octyl]benzenesulfonamide

[0298]

[0299] Using the general method of Example 242,1-(8-aminooctyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (1.0 g, 2.72mmol) was reacted with benzenesulfonyl chloride (350 μL, 2.72 mmol) toprovide 1.38 g ofN-[8-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)octyl]benzenesulfonamideas an off white powder, m.p. 143-144° C. Analsysis: Calculated forC₂₈H₃₇N₅O₂S: % C, 66.24; % H, 7.35; % N, 13.79; Found: % C, 66.08; % H,7.25; % N, 13.72. Karl Fisher titration found 0.23% water.

[0300]¹H NMR (300 MHz, DMSO-d₆) δ 7.98 (d, J=7.8 Hz, 1H), 7.77 (m, 2H),7.62-7.53 (m, 5H), 7.41 (m, 1H), 7.25 (m, 1H), 6.47 (s, 2H), 4.47 (m,2H), 2.90 (m, 2H), 2.70 (q, J=6.3 Hz, 2H), 1.78 (m, 4H), 1.49-1.17 (m,12H), 0.95 (t, J=7.3, 3H);

[0301]¹³C NMR (125 MHz, DMSO-d₆) 153.3, 152.0, 145.0, 141.0, 132.5,129.5, 126.82, 126.76, 126.7, 126.6, 121.5, 120.3, 120.2, 115.1, 45.1,42.8, 30.0, 29.2, 28.8, 28.7, 26.5, 26.2, 26.1, 22.3, 14.2, 14.1;

[0302] MS m/z 507 (M+1).

EXAMPLE 249N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}benzenesulfonamide

[0303]

[0304] Using the general method of Example 242,1-(3-aminopropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine(1.53 g, 5.11 mmol) was reacted with benzenesulfonyl chloride (993 mg,5,62 mmol) to provide 1.37 g ofN-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}benzenesulfonamideas a white powder, m.p. 149-151° C. Analysis: Calculated forC₂₂H₂₅N₅O₃S: % C, 60.12; % H, 5.73; % N, 15.93; Found: % C, 60.40; % H,5.82; % N, 15.85.

EXAMPLE 250N-[4-(4-amino-2-pentyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamide

[0305]

[0306] Using the general method of Example 245,1-(4-aminobutyl)-2-pentyl-1H-imidazo[4,5-c]quinolin-4-amine (1.50 g, 4.6mmol) was reacted with methanesulfonyl chloride (0.57 mL, 7.4 mmol) toprovide 636 mg ofN-[4-(4-amino-2-pentyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamideas an off white solid, m.p. 136.8-138.1° C. Analysis: Calculated forC₂₀H₂₉N₅O₂S: % C, 59.53; % H, 7.24; % N, 17.35; Found: % C, 59.50; % H,7.31; % N, 16.80.

EXAMPLE 251N-[4-(4-amino-2-pentyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]benzenesulfonamide

[0307]

[0308] Using the general method of Example 232,1-(4-aminobutyl)-2-pentyl-1H-imidazo[4,5-c]quinolin-4-amine (1.00 g, 3.1mmol) was reacted with benzenesulfonyl chloride (0.51 mL, 4.0 mmol) toprovide 0.35 g ofN-[4-(4-amino-2-pentyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]benzenesulfonamideas a yellow crystalline solid. Analysis: Calculated for C₂₅H₃₁N₅O₂S0.5H₂O: % C, 63.27; % H, 6.80; % N, 14.76; Found: % C, 62.99; % H, 6.61;% N, 14.42.

EXAMPLE 252N-[8-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)octyl]methanesulfonamide

[0309]

[0310] Using the general method of Example 242,1-(8-aminooctyl)-1H-imidazo[4,5-c]quinolin-4-amine (3.85 mmol) wasreacted with methanesulfonyl chloride (310 μL, 3.85 mmol) to provide0.43 g ofN-{8-[4-amino-1H-imidazo[4,5-c]quinolin-1-yl]octyl}methanesulfonamide asan off white powder, m.p. 153-155° C. Analysis: Calculated forC₁₉H₂₇N₅O₂S: % C, 58.59; % H, 6.99; % N, 17.98; % S, 8.23; Found: % C,58.40; % H, 6.99; % N, 17.71; % S, 8.14.

[0311]¹H NMR (300 MHz, DMSO-d₆) δ 8.20 (s, 1H), 8.03 (d, J=7.8 Hz, 1H),7.63 (d, J=8.3 Hz, 1H), 7.45 (m, 1H), 7.27 (m, 1H), 6.91 (m, 1H), 6.63(d, 2H), 4.59 (m, 2H), 2.89 (m, 2H), 2.86 (s, 3H), 1.86 (m, 2H),1.41-1.25 (m, 10H);

[0312]¹³C NMR (125 MHz, DMSO-d₆) 152.5, 145.2, 143.2, 132.0, 128.5,127.1, 126.5, 121.6, 120.8, 115.2, 46.9, 42.8, 39.6, 30.0, 29.7, 28.81,28.78, 26.4, 26.1;

[0313] MS m/z 390 (M+1).

EXAMPLE 253N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}-4-methylbenzenesulfonamide

[0314]

[0315] Using the general method of Example 242,1-(3-aminopropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine(1.53 g, 5.11 mmol) was reacted with p-toluenesulfonyl chloride (1.07 g,5,62 mmol) to provide 750 mg ofN-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}-4-methylbenzenesulfonamideas a solid, m.p. 189-191° C. Analysis: Calculated for C₂₃H₂₇N₅O₃S0.50H₂O: % C, 59.72; % H, 6.10; % N, 15.14; Found: % C, 59.73; % H,5.95; % N, 15.08.

EXAMPLE 254N-[4-(4-amino-2-pentyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamide

[0316]

[0317] A solution of1-(4-aminobutyl)-2-pentyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine(1.50 g, 3.7 mmol) in chloroform (150 mL) was chilled in an acetone/icebath. Methanesulfonic anhydride (0.79 g, 3.7 mmol) was slowly added.After 1.75 hr, 0.018 g of anhydride was added. At 2.5 hrs 0.079 g ofanhydride was added. After 3 hrs, the reaction mixture was washed withaqueous 1% sodium carbonate solution (3×150 mL). The organic layer wasdried over magnesium sulfate and then concentrated under reducedpressure to provide 2.2 g of a light yellow residue. The residue wascombined with aqueous 1% sodium carbonate solution (200 mL) and the pHwas adjusted to 13 by the addition of solid sodium carbonate and 50%sodium hydroxide. The organic phase was separated, washed with aqueous1% sodium carbonate solution (3×200 mL), dried over magnesium sulfateand then concentrated under reduced pressure to provide 2.18 g of abrown residue. This material was slurried with methyl acetate. Theresulting solid was isolated to provide 1.25 g ofN-[4-(4-amino-2-pentyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamideas a white solid, m.p. 167.0-167.8° C. Analysis: Calculated forC₂₀H₃₃N₅O₂S: % C, 58.94; % H, 8.16; % N, 17.18; Found: % C, 58.79; % H,7.92; % N, 17.02.

EXAMPLE 255N-{3-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}methanesulfonamide

[0318]

[0319] A mixture of1-(3-aminopropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine(2.0 g, 6.7 mmol), triethylamine (1.5 mL, 15 mmol) and acetonitrile (75mL) was heated until a solution was obtained. Methanesulfonic anhydride(1.28 g, 7.4 mmol) was added in a single portion. After 5 minutes asmall amount of anhydride was added. The reaction mixture was allowed tostir overnight. The reaction mixture was quenched with aqueous 1% sodiumcarbonate solution. The aqueous layer was extracted with chloroform. Theorganics were dried over magnesium sulfate, filtered and thenconcentrated under reduced pressure. The residue was dried under highvacuum for 3 hours to provide 2.73 g of a glassy solid. This materialwas recrystallized from methanol to provide 1.38 g ofN-{3-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}methanesulfonamide,m.p. 208.2-209.6° C. Analysis: Calculated for C₁₇H₂₃N₅O₃S: % C, 54.09; %H, 6.14; % N, 18.55; Found: % C, 53.97; % H, 6.29; % N, 18.32.

EXAMPLE 256N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2,2-dimethylpropyl}methanesulfonamide

[0320]

[0321] Using the general method of Example 242,1-(3-amino-2,2-dimethylpropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine(0.22 g, 0.672 mmol) was reacted with methanesulfonyl chloride (125 μL)to provide 270 mg ofN-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2,2-dimethylpropyl}methanesulfonamideas a cream colored powder, m.p. 204.0-206.0° C. Analysis: Calculated forC₁₉H₂₇N₅O₃S 0.50H₂O: % C, 55.05; % H, 6.81; % N, 16.89; % S, 7.74;Found: % C, 55.10; % H, 6.58; % N, 17.23; % S, 7.51. % H₂O calculated:2.17; found: 2.28 (Karl Fisher).

[0322]¹H NMR (300 MHz, DMSO-d₆) δ 8.36 (d, J=8.3 Hz, 1H), 7.59 (d, J=8.3Hz, 1H), 7.38 (m, 2H), 7.20 (m, 1H), 6.49 (s, 2H), 4.81 (br s, 1H), 4.39(br s, 1H), 3.82 (m, 2H), 3.27 (s, 3H), 3.19 (br s, 2H), 3.02 (d, J=6.8Hz, 2H), 2.94 (s, 3H), 0.82 (br s, 6H);

[0323]¹³C NMR (125 MHz, DMSO-d₆) δ 152.5, 152.0, 145.3, 133.9, 126.8,126.7, 126.6, 121.5, 120.7, 115.8, 71.0, 58.5, 51.8, 51.5, 39.7, 39.0,28.3, 24.4, 23.1;

[0324] MS m/z 406 (M+H).

EXAMPLE 257N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}-5-(dimethylamino)naphthalene-1-sulfonamide

[0325]

[0326] Using the general method of Example 245 except that chloroformwas used as the solvent,1-(3-aminopropyl)-2-(methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine(1.53 g, 5.11 mmol) was reacted with5-dimethylamino-1-naphthalenesulfonyl chloride (5.87 mmol) to provide1.45 g ofN-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}-5-(dimethylamino)naphthalene-1-sulfonamideas a yellow solid, m.p. 210-215° C. Analysis: Calculated for C₂₈H₃₂N₆O₃S1.50H₂O: % C, 60.09; % H, 6.30; % N, 15.02; Found: % C, 59.89; % H,6.22; % N, 14.86.

EXAMPLE 258N-[3-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]methanesulfonamide

[0327]

[0328] Using the general method of Example 255,1-(3-aminopropyl)-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (2.0 g, 7.8mmol) was reacted with methanesulfonic anhydride (1.49 g, 8.6 mmol) toprovide 1.2 g ofN-[3-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]methanesulfonamideas a solid, m.p. 236.0-238.0° C. Analysis: Calculated for C₁₅H₁₉N₅O₂S0.25H₂O: % C, 53.32; % H, 5.82; % N, 20.72; Found: % C, 53.35; % H,5.72; % N, 20.57.

EXAMPLE 259N-{3-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl]propyl}methanesulfonamide

[0329]

[0330] Using the general method of Example 255,1-(3-aminopropyl)-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine(2.0 g, 6.6 mmol) was reacted with methanesulfonic anhydride (1.26 g,7.3 mmol) to provide 630 mg ofN-{3-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl]propyl}methanesulfonamideas a solid, m.p. 150.0-152.0° C. Analysis: Calculated for C₁₇H₂₇N₅O₃S: %C, 53.52; % H, 7.13; % N, 18.36; Found: % C, 53.27; % H, 7.12; % N,18.37.

EXAMPLE 260N-{3-[4-amino-2-(ethoxymethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl]propyl}methanesulfonamide

[0331]

[0332] Using the general method of Example 255, except that chloroformwas used in place of aceotnitrile,1-(3-aminopropyl)-2-(2-ethoxymethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine(2.6 g, 8.35 mmol) was reacted with methanesulfonic anhydride (3+g) toprovide 850 mg ofN-{3-[4-amino-2-(2-ethoxymethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl]propyl}methanesulfonamideas a solid, m.p. 212.0-214.0° C. Analysis: Calculated for C₁₇H₂₇N₅O₃S: %C, 53.52; % H, 7.13; % N, 18.36; Found: % C, 53.25; % H, 7.16; % N,18.09.

EXAMPLE 261N-{3-[4-amino-2-(3-phenoxypropyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}methanesulfonamide

[0333]

[0334] Using the general method of Example 242, except that chloroformwas used in place of dichloromethane,1-(3-aminopropyl)-2-(3-phenoxypropyl)-1H-imidazo[4,5-c]quinolin-4-amine(2.00 g, 5.32 mmol) was reacted with methanesulfonyl chloride (3+g) toprovide 1.38 g ofN-{3-[4-amino-2-(3-phenoxypropyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}methanesulfonamideas a solid, m.p. 176-178° C. Analysis: Calculated for C₂₃H₂₇N₅O₃S: % C,60.91; % H, 6.00; % N, 15.44; Found: % C, 60.71; % H, 5.98; % N, 15.45.

EXAMPLE 262N-{4-[4-amino-2-(3-phenoxypropyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}methanesulfonamide

[0335]

[0336] Using the general method of Example 255, except that pyridine wasused in place of acetonitrile,1-(3-aminobutyl)-2-(3-phenoxypropyl)-1H-imidazo[4,5-c]quinolin-4-amine(2.00 g, 5.1 mmol) was reacted with an excess of methanesulfonicanhydride to provide 1.36 g ofN-{4-[4-amino-2-(3-phenoxypropyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}methanesulfonamideas a solid, m.p. 156.4-157.1° C. Analysis: Calculated for C₂₄H₂₉N₅O₃S: %C, 60.48; % H, 6.34; % N, 14.69; Found: % C, 60.75; % H, 6.36; % N,14.31.

EXAMPLE 263N-[4-(4-amino-2-methyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamideHydrochloride

[0337]

[0338] Using the general method of Example 254,1-(4-aminobutyl)-2-methyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine(1.00 g, 3.7 mmol) was reacted with methanesulfonic anhydride (0.96 g,5.5 mmol) in the presence of triethylamine (0.76 mL, 5.5 mmol) toprovide 0.55 g of the free base of the desired product. This materialwas combined with methanol (˜20 mL), warmed, allowed to cool to ambienttemperature and then filtered to remove some insoluble material. Thefiltrate was reduced to a volume of 10 mL and then combined with 1Nhydrochloric acid (3 mL). Diethyl ether (15 mL) was added and then themixture was concentrated under reduced pressure. The resulting residuewas slurried with isopropyl alcohol to provide a white solid which wasisolated by filtration and then dried to provide 0.46 g ofN-[4-(4-amino-2-methyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamidehydrochloride, m.p. >250° C. Analysis: Calculated for C₁₆H₂₅N₅O₂S 1.00HCl 1.00H₂O: % C, 47.34; % H, 6.95; % N, 17.25; Found: % C, 47.40; % H,6.49; % N, 17.22.

EXAMPLE 264N-[2-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]-4-methylbenzenesulfonamide

[0339]

[0340] Triethylamine (1.1 g, 15.9 mmol) was added to a cooled (0° C.)solution of 1-(2-aminoethyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine(3.0 g, 10.6 mmol) in 1-methyl-2-pyrrolidinone (100 mL). A solution oftosyl chloride (2.11 g, 11.1 mmol) in 1-methyl-2-pyrrolidinone (20 mL)was slowly added in a dropwise fashion. The reaction was allowed to warmto ambient temperature and was maintained overnight. The reaction waspoured into water (1500 mL) and adjusted to pH 9. A white precipitatewas isolated by filtration and then recrystallized from acetonitrile (60mL) to provide 3.9 g ofN-[2-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]-4-methylbenzenesulfonamide,m.p. 187.0-188.0° C. Analysis: Calculated for C₂₃H₂₇N₅O₂S 0.3H₂O: % C,62.29; % H, 6.28; % N, 15.79; Found: % C, 62.52; % H, 6.36; % N, 15.88.

EXAMPLE 265N-[2-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]methanesulfonamide

[0341]

[0342] Methanesulfonyl chloride (1.27 g, 11.1 mmol) was slowly added toa solution of 1-(2-aminoethyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine(3.0 g, 10.6 mmol) in pyridine (60 mL). The reaction was maintained atambient temperature overnight and then it was concentrated to dryness.The residue was combined with warm dichloroethane and water and thenfiltered to provide an off white solid. The dichloroethane layer wasconcentrated to provide an off white solid. The two solids were combinedand then recrystallized from N,N-dimethylformamide to provide 1.1 g ofN-[2-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]methanesulfonamideas a white solid, m.p. 210.0-211.0° C. Analysis: Calculated forC₁₇H₂₃N₅O₂S: % C, 56.49; % H, 6.41; % N, 19.37; Found: % C, 56.45; % H,6.49; % N, 19.50.

EXAMPLE 2661-[4-(1,1-dioxidoisothiazolidin-2-yl)butyl]-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine

[0343]

[0344] Under a nitrogen atmosphere,1-(4-aminobutyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine(500 mg, 1.6 mmol) was dissolved in dichloromethane (5 mL) andtriethylamine (0.33 mL, 2.4 mmol). 3-Chloropropylsulfonyl chloride (0.19mL, 1.6 mmol) was added dropwise and the reaction was stirred for 2hours. The solvent was removed in vacuo. The residue was dissolved inN,N-dimethylformamide (5 mL) and 1,8-diazabicyclo[5.4.0]undec-7-ene(0.48 mL, 3.2 mmol) was added. The reaction was stirred for 72 hours andthen poured into water and extracted with dichloromethane. The organiclayer was washed with water followed by brine; dried (Na₂SO₄); decantedand evaporated to yield crude product as a brown oil. Purificationinvolved flash column chromatography (silica gel, gradient elution withmethanol/dichloromethane 100:0 to 94:6) followed by recrystallizationfrom acetonitrile to provide 289 mg of1-[4-(1,1-dioxidoisothiazolidin-2-yl)butyl]-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amineas a yellow crystalline solid, m.p. 156.4-157.7° C.

[0345]¹H-NMR (500 MHz, DMSO-d₆) δ 8.04 (d, J=7.4 Hz, 1H), 7.62 (dd,J=8.3, 1.2 Hz, 1H); 7.42 (ddd, J=8.2, 7.0, 1.2 Hz, 1H), 7.26 (ddd,J=8.2, 7.0, 1.2 Hz, 1H), 6.48 (bs, 2H), 4.54 (t, J=7.6 Hz, 2H), 3.84 (t,J=6.7 Hz, 2H), 3.29 (s, 3H), 3.22-3.12 (m, 6H), 2.93 (t, J=6.6 Hz, 2H),2.23-2.13 (m, 2H), 1.90-1.65 (m, 4H);

[0346]¹³C-NMR (125 MHz, DMSO-d₆) 6151.6, 150.6, 144.8, 132.2, 126.5,126.3, 121.2, 120.0, 114.7, 70.2, 58.1, 46.5, 46.1, 44.5, 43.6, 27.1,24.1, 18.3;

[0347] Anal calcd for C₂₀H₂₇N₅O₃S: % C, 57.53; % H, 6.52; % N, 16.77; %S, 7.68. Found: % C, 57.52; % H, 6.67; % N, 16.88; % S, 7.71.

EXAMPLE 2672-butyl-1-[4-(1,1-dioxidoisothiazolidin-2-yl)butyl]-1H-imidazo[4,5-c]quinolin-4-amine

[0348]

[0349] Using the general method of Example 266 except that1-methyl-2-pyrrolidinone was used in place of dichloromethane,1-(4-aminobutyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (5.0 g, 16.0mmol) was reacted with 3-chloropropanesulfonyl choride (2.83 g, 16.0mmol) to provide 0.75 g of2-butyl-1-[4-(1,1-dioxidoisothiazolidin-2-yl)butyl]-1H-imidazo[4,5-c]quinolin-4-amineas a white solid, m.p. 173.0-176.0° C.

[0350]¹H-NMR (300 MHz, DMSO-d₆) δ 8.30 (d, J=8.1 Hz, 1H), 7.62 (d, J=8.2Hz, 1H), 7.41 (t, J=7.6 Hz, 1H), 7.26 (t, J=8.0 Hz, 1H), 6.48 (bs, 2H),4.51 (t, J=7.5 Hz, 2H), 3.18-3.11 (m, 4H), 2.96-2.89 (m, 4H), 2.22-2.12(m, 2H), 1.92-1.63 (m, 6H), 1.45 (sextet, J=7.4 Hz, 2H), 0.96 (t, J=7.3Hz, 3H);

[0351]¹³C-NMR (75 MHz, DMSO-d₆) δ 153.0, 151.7, 144.7, 132.2, 126.4,126.2, 121.1, 120.0, 114.7, 46.5, 46.1, 44.3, 43.6, 29.7, 27.1, 26.1,24.1, 22.0, 18.3, 13.8;

[0352] MS (CI) m/e 416.2124 (416.2120 calcd for C₂₁H₃₀N₅O₂S, M+H);

[0353] Anal calcd for C₂₁H₂₉N₅O₂S: % C, 60.70; % H, 7.03; % N, 16.85; %S, 7.72. Found: % C, 60.67; % H, 6.94; % N, 17.02; % S, 7.42.

EXAMPLE 268N-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}methanesulfonamide

[0354]

[0355] Part A

[0356] A stirred solution of 4-chloro-3-nitroquinoline (17.3 g, 83.2mmol) in 200 mL of anhydrous CH₂Cl₂, under N₂, was treated withtriethylamine (23.2 mL, 166.4 mmol) and 1,2-diamino-2-methylpropane(9.57 mL, 91.5 mmol). After stirring overnight, the reaction mixture wasdiluted with 800 mL of CHCl₃ washed with H₂O (3×300 mL) and brine (300mL). The organic portion was dried over Na₂SO₄ and concentrated to give2-methyl-N¹-(3-nitroquinolin-4-yl)propane-1,2-diamine (21.0 g) as abright yellow solid.

[0357] Part B

[0358] A solution of2-methyl-N¹-(3-nitroquinolin-4-yl)propane-1,2-diamine (2.60 g, 10.0mmol) in 50 mL of THF, under N₂, was cooled to 0° C. and treated with 10mL of 1N NaOH solution. Di-tert-butyl dicarbonate (2.18 g, 10.0 mmol)was then added to the rapidly stirred solution. The reaction mixture wasthen allowed to warm to ambient temperature and was stirred overnight.An additional 400 mg of di-tert-butyl dicarbonate was added and stirringwas continued for 3 d. The reaction was then treated with ethyl acetate(200 mL) and washed with H₂O (2×) and brine. The organic portion wasdried over Na₂SO₄ and concentrated to give a yellow solid that wastiturated with 10% EtOAc/hexanes. The solid was isolated by filtrationand dried under vacuum overnight to give tert-butyl1,1-dimethyl-2-[(3-nitroquinolin-4-yl)amino]ethylcarbamate (2.80 g) as ayellow powder.

[0359] Part C

[0360] A solution of tert-butyl1,1-dimethyl-2-[(3-nitroquinolin-4-yl)amino]ethylcarbamate (3.50 g, 9.72mmol), in 150 mL of toluene was treated with 0.3 g of 5% Pt on carbonand shaken under H₂ (3 atm, 3 Kg/cm²) for 6 h. The solution was thenfiltered through a Celite pad and concentrated to give 3.04 g of crudetert-butyl 2-[(3-aminoquinolin-4-yl]-1,1-dimethylethylcarbamate as alight orange foam.

[0361] Part D

[0362] A solution of tert-butyl2-[(3-aminoquinolin-4-yl]-1,1-dimethylethylcarbamate (3.04 g, 9.21 mmol)in 50 mL of CH₂Cl₂ was cooled to 0° C. and treated with triethylamine(1.41 mL, 10.13 mmol) and ethoxyacetyl chloride (1.02 mL, 10.17 mmol).After 2 h, the reaction mixture was concentrated under reduced pressure.The resulting syrup was taken up in 100 mL of EtOH and treated with 4.5mL of triethylamine. The solution was heated to reflux overnight. Thereaction mixture was concentrated and taken up in 100 mL of CH₂Cl₂ andwashed with H₂O (2×) and brine. The organic portion was dried overNa₂SO₄ and concetrated. The resulting syrup was purified by columnchromatography (SiO₂, 80% EtOAc/hexanes) to give tert-butyl2-[2-(ethoxymethy)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethylcarbamate(1.57 g) as a peach colored foam.

[0363] Part E

[0364] A solution of tert-butyl2-[2-(ethoxymethy)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethylcarbamate(1.57 g, 3.94 mmol) in 30 mL of CH₂Cl₂ was treated with3-chloroperoxybenzoic acid (77%, 1.01 g, 4.57 mmol). After stirring for2 h, the reaction mixture was treated with 30 mL of additional CH₂Cl₂and was washed with 1% Na₂CO₃ solution (2×30 mL), H₂O and brine. Theorganic portion was then dried over Na₂SO₄ and concentrated to givetert-butyl2-[2-(2-(ethoxymethyl)-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethylcarbamate(1.58 g) as a light brown foam.

[0365] Part F

[0366] A solution of tert-butyl2-[2-(2-(ethoxymethyl)-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethylcarbamate(1.57 g, 3.79 mmol) in 20 mL of 1,2-dichloroethane was heated to 70° C.and treated with 2 mL of concentrated NH₄OH solution. To the rapidlystirred solution was added solid p-toluenesulfonyl chloride (795 mg,4.17 mmol). The reaction mixture was then sealed in a pressure vesseland heating was continued for 2 h. The reaction mixture was then cooledand treated with 50 mL of CHCl₃. The reaction mixture was then washedwith H₂O, 1% Na₂CO₃ solution (3×) and brine. The organic portion wasdried over Na₂SO₄ and concentrated to give the product as a light brownoil. The resulting oil was purified by column chromatography (SiO₂, 2-5%MeOH/CHCl₃) to give tert-butyl2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethylcarbamate(1.26 g) as a light yellow foam.

[0367] Part G

[0368] Tert-butyl2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethylcarbamate(1.26 g, 3.05 mmol) was dissolved in 10 mL of EtOH and treated with 10mL of 2 M HCl in EtOH. After heating at reflux for 2 h, the reactionmixture was cooled and concentrated under reduced pressure. Theresulting yellow solid was dissolved in 50 mL of H₂O and extracted withCHCl₃ (20 mL). The organic layer was discarded and the aqueous portionwas made basic (pH ˜12) by addition of concentrated NH₄OH solution. Thiswas then extracted with CHCl₃ (4×20 mL) and the combined organicportions were dried with Na₂SO₄ and concentrated to give1-(2-amino-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinoline-4-amine(808 mg) as a light brown powder.

[0369] m.p. 161.0-162.0° C.;

[0370] MS m/z 314 (M+H);

[0371]¹H NMR (300 MHz, d₆-DMSO) δ 8.30 (d, J=7.7 Hz, 1H), 7.59 (dd,J=1.2, 8.3 Hz, 1H), 7.40 (ddd, J=1.0, 7.2, 8.1 Hz, 1H), 7.21 (ddd,J=1.2, 7.0, 8.2 Hz, 1H), 6.57 (s, 2H), 4.94 (br s, 2H), 4.61 (br s, 2H),3.52 (q, J=7.0 Hz, 2H), 1.61 (s, 2H), 1.31 (t, J=7.0 Hz, 3H), 1.07 (s,6H);

[0372]¹³C NMR (75 MHz, d₆-DMSO) δ 152.4, 151.1, 145.7, 134.3, 126.8,126.7, 121.7, 120.8, 115.7, 65.6, 65.2, 55.8, 52.5, 29.2, 15.4.

[0373] Anal. Calcd for C₁₇H₂₃N₅O: % C, 65.15; % H, 7.40; % N, 22.35.Found: % C, 65.04; % H, 7.52; % N, 22.07.

[0374] Part H

[0375]1-(2-Amino-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinoline-4-amine(111 mg, 0.355 mmol) was dissolved in 5 mL of anhydrous CH₂Cl₂ andcooled to 0° C. under N₂. To the stirred solution were added Et₃N (99μL, 0.71 mmol) and methanesulfonyl chloride (28 μL, 0.36 mmol) and thereaction was allowed to warm to ambient temperature overnight. Thereaction mixture was then quenched by addition of saturated NaHCO₃solution (5 mL). The organic layer was separated and washed with H₂O(2×5 mL) and brine, dried over Na₂SO₄ and concentrated under reducedpressure to give a tan foam. Purification by column chromatography(SiO₂, 2.5%-5% MeOH/CHCl₃) gaveN-{2-[4-amino-2-(ethoxymethyl)-H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}methanesulfonamide(75 mg) as a white foam.

[0376] m.p. 105.0-110.0° C.;

[0377] MS m/z 392 (M+H)⁺;

[0378]¹H NMR (300 MHz, CDCl₃) δ 8.06 (dd, J=1.0, 8.3 Hz, 1H), 7.79 (dd,J=1.1, 8.4 Hz, 1H), 7.51 (ddd, J=1.3, 7.0, 8.4 Hz, 1H), 7.31 (ddd,J=1.3, 7.0, 8.3 Hz, 1H), 5.90 (br s, 1H), 5.51 (br s, 2H), 4.96 (s, 2H),4.92 (br s, 2H), 3.74 (q, J=7.0 Hz, 2H), 3.02 (s, 3H), 1.55 (br s, 6H),1.29 (t, J=7.0 Hz, 3H);

[0379]¹³C NMR (75 MHz, CDCl₃) δ 152.0, 150.8, 145.5, 135.2, 127.8,127.6, 127.2, 122.2, 120.6, 116.0, 67.2, 65.4, 58.4, 55.8, 45.3, 26.6,15.3.

[0380] Anal. Calcd for C₁₈H₂₅N₅O₃S.0.75H₂O: C, 53.38; % H, 6.60; % N,17.29. Found: % C, 53.49; % H, 6.23; % N, 16.93.

EXAMPLE 269N-[4-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]ethanesulfonamide

[0381]

[0382] Using the general method of Example 232,1-(4-aminobutyl)-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (1.00 g, 3.7mmol) was reacted with ethanesulfonyl chloride (2.11 mL, 22.3 mmol) toprovide 85 mg ofN-[4-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]ethanesulfonamideas an off-white solid, m.p. 210.7-211.6° C.

EXAMPLE 270N-{4-[4-amino-2-(cyclopropylmethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}methanesulfonamide

[0383]

[0384] Using the general method of Example 239 Part B except thatchloroform was used instead of dichloromethane,1-(4-aminobutyl)-2-(cyclopropylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine(1.00 g, 3.2 mmol) was reacted with methanesulfonic anhydride (1.29 g,7.4 mmol) to provide 0.42 g ofN-{4-[4-amino-2-(cyclopropylmethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}methanesulfonamideas a brown solid, m.p. 199.7-200.7° C.

Cytokine Induction in Human Cells

[0385] An in vitro human blood cell system was used to assess cytokineinduction by compounds of the invention. Activity is based on themeasurement of interferon and tumor necrosis factor (α) (IFN and TNF,respectively) secreted into culture media as described by Testerman et.al. In “Cytokine Induction by the Immunomodulators Imiquimod andS-27609”, Journal of Leukocyte Biology, 58, 365-372 (September, 1995).

[0386] Blood Cell Preparation for Culture

[0387] Whole blood is collected by venipuncture into EDTA vacutainertubes from healthy human donors. Peripheral blood mononuclear cells(PBMCs) are separated from whole blood by density gradientcentrifugation using Histopaque®-1077 (Sigma Chemicals, St. Louis, Mo.).The PBMCs are suspended at 3-4×10⁶ cells/mL in RPMI 1640 mediumcontaining 10% fetal bovine serum, 2 mM L-glutamine and 1%penicillin/streptomycin solution (RPMI complete). The PBMC suspension isadded to 48 well flat bottom sterile tissue culture plates (Costar,Cambridge, Mass. or Becton Dickinson Labware, Lincoln Park, N.J.)containing an equal volume of RPMI complete media containing testcompound.

[0388] Compound Preparation

[0389] The compounds are solubilized in dimethyl sulfoxide (DMSO). TheDMSO concentration should not exceed a final concentration of 1% foraddition to the culture wells.

[0390] Incubation

[0391] The solution of test compound is added at 60 μM to the first wellcontaining RPMI complete and serial (three fold or ten fold) dilutionsare made. The PBMC suspension is then added to the wells in an equalvolume, bringing the test compound concentrations to the desired range.The final concentration of PBMC suspension is 1.5-2×10⁶ cells/mL. Theplates are covered with sterile plastic lids, mixed gently and thenincubated for 18 to 24 hours at 37° C. in a 5% carbon dioxideatmosphere.

[0392] Separation

[0393] Following incubation the plates are centrifuiged for 5-10 minutesat 1000 rpm (˜200×g) at 4° C. The cell culture supernatant is removedwith a sterile polypropylene pipet and transferred to sterilepolypropylene tubes. Samples are maintained at −30 to −70° C. untilanalysis. The samples are analyzed for interferon (α) and tumor necrosisfactor (α) by ELISA

[0394] Interferon (α) and Tumor Necrosis Factor (α) Analysis by ELISA

[0395] Interferon (α) concentration is determined by ELISA using a HumanMulti-Species kit from PBL Biomedical Laboratories, New Brunswick, N.J.

[0396] Tumor necrosis factor (α) (TNF)concentration is determined usingELISA kits available from Genzyme, Cambridge, Mass.; R&D Systems,Minneapolis, Minn.; or Pharmingen, San Diego, Calif.

[0397] The table below lists the lowest concentration found to induceinterferon and the lowest concentration found to induce tumor necrosisfactor for each compound. A “**” indicates that no induction was seen atany of the tested concentrations (0.12, 0.37, 1.11, 3.33, 10 and 30 μM).A “***” indicates that no induction was seen at any of the testedconcentrations (0.0001, 0.001, 0.01, 0.1, 1 and 10 μM). CytokineInduction in Human Cells Example Lowest Effective Concentration (μM)Number Interferon Tumor Necrosis Factor 1 0.12 3.33 2 ** ** 3 0.01 ** 60.00017 1.11 7 0.01 ** 9 0.04 ** 11 0.01 1.11 13 10 ** 17 1.11 3.33 183.33 ** 19 0.12 3.33 20 0.12 3.33 21 1.11 30 22 0.37 ** 23 0.12 10 240.12 30 25 3.33 ** 26 10 ** 27 1.11 30 28 1.11 30 29 0.37 10 30 1.11 **31 1.11 ** 32 1.11 ** 33 1.11 10 34 0.04 0.37 35 1.11 10 36 0.0015 3.3337 0.01 1.11 38 0.0015 0.37 40 0.0015 3.33 41 0.01 ** 42 0.01 ** 43 0.04** 44 0.0015 1.11 45 0.37 ** 46 0.37 ** 47 0.37 ** 48 0.37 10 50 0.12 **51 0.0015 0.37 52 0.12 10 53 0.01 3.33 54 10 ** 55 3.33 ** 56 ** ** 573.33 ** 58 3.33 ** 59 3.33 ** 60 ** ** 61 3.33 ** 62 ** ** 63 ** ** 643.33 ** 65 3.33 ** 66 ** 30 67 10 ** 68 10 ** 69 10 ** 70 ** ** 71 ** 3072 3.33 ** 73 0.001 0.1 74 0.001 0.01 75 *** *** 76 *** *** 77 0.001 178 0.001 0.1 79 0.01 1 80 1 10 81 0.001 1 82 0.001 1 83 0.001 1 84 1 1085 1 *** 86 0.01 1 87 0.001 1 88 0.01 1 89 0.001 1 90 0.01 1 91 0.01 192 0.1 10 93 0.001 0.1 94 0.001 1 95 0.001 1 96 1 *** 97 0.1 10 98 1 ***99 0.1 10 100 0.01 10 101 0.01 10 102 0.001 10 103 0.1 10 104 0.01 ***105 1 10 106 1 1 107 1 *** 108 0.1 10 109 1 10 110 10 *** 111 0.001 10112 0.0001 *** 113 0.0001 *** 114 0.01 *** 116 0.001 1 117 0.0001 1 1200.0001 1 121 0.0001 10 122 0.0001 1 123 0.0001 10 127 0.0001 10 1280.0001 1 131 0.0001 1 138 0.0001 10 148 0.0001 1 152 0.0001 10 154 0.00110 158 0.0001 1 159 0.0001 0.1 160 0.001 1 161 0.01 10 184 0.0001 1 2000.01 0.1 202 0.0001 1 203 0.0001 1 204 0.0001 1 205 0.0001 1 206 1 ***207 0.001 1 208 0.0001 1 209 0.0001 0.1 210 0.0001 1 211 0.0001 1 2120.0001 0.01 213 0.0001 1 214 0.01 10 215 0.01 1 217 1 *** 218 0.0001 1220 0.0001 1 221 0.0001 1 224 0.0001 10 226 0.0001 0.1 227 0.001 *** 2290.0001 0.1 230 0.0001 1 231 0.0001 1 232 0.12 1.11 233 0.37 1.11 2341.11 1.11 235 0.04 1.11 236 0.01 0.12 237 0.37 0.04 238 0.04 0.37 2390.01 1.11 240 0.37 3.33 241 0.12 1.11 242 0.01 0.01 243 0.01 0.01 2440.01 0.01 245 3.33 ** 246 1.11 3.33 247 0.01 0.01 248 0.12 0.01 249 0.011.11 250 0.01 0.12 251 0.12 10 252 0.37 1.11 253 0.04 0.12 254 0.01 1.11255 0.12 3.33 256 0.01 0.04 257 1.11 3.33 258 0.37 10 259 0.01 10 2600.01 0.37 261 ** 10 262 ** 10 263 0.12 ** 264 1.11 1.11 265 0.01 0.04267 0.01 0.12

[0398] The present invention has been described with reference toseveral embodiments thereof. The foregoing detailed description andexamples have been provided for clarity of understanding only, and nounnecessary limitations are to be understood therefrom. It will beapparent to those skilled in the art that many changes can be made tothe described embodiments without departing from the spirit and scope ofthe invention. Thus, the scope of the invention should not be limited tothe exact details of the compositions and structures described herein,but rather by the language of the claims that follow.

What is claimed is:
 1. A compound of the formula (I):

wherein R₁ is —C₂₋₆ alkyl-NR₃—SO₂—X—R₄ or —C₂₋₆ alkyl-NR₆—SO₂—R₇; X is abond or —NR₅—; R₄ is alkyl, aryl, or heteroaryl; R₂ is selected from thegroup consisting of: -hydrogen; -alkyl; -alkenyl; -aryl; -substitutedaryl; -heteroaryl; -substituted heteroaryl; -alkyl-O-aryl;alkyl-O-alkyl; alkyl-O-alkenyl; and alkyl or alkenyl substituted by oneor more substituents selected from the group consisting of: —OH;-halogen; —N(R₃)₂; —CO—N(R₃)₂; —CO—C₁₋₁₀ alkyl; —CO—O-_(C1-10) alkyl;—N₃; -aryl; -substituted aryl; -heteroaryl; -substituted heteroaryl;-heterocyclyl; -substituted heterocyclyl; —CO-aryl; —CO-(substitutedaryl); —CO-heteroaryl; and —CO-(substituted heteroaryl); each R₃ isindependently selected from the group consisting of hydrogen and C₁₋₁₀alkyl; R₅ is selected from the group consisting of hydrogen and C₁₀alkyl, or R₄ and R₅ can combine to form a 3 to 7 membered heterocyclicor substituted heterocyclic ring; R₆ is selected from the groupconsisting of hydrogen and C₁₋₁₀ alkyl; R₇ is selected from the groupconsisting of hydrogen and C₁₋₁₀ alkyl, or R₆ and R₇ can combine to forma 3 to 7 membered heterocyclic or substituted heterocyclic ring; n is 0to 4 and each R present is independently selected from the groupconsisting of C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, halogen and trifluoromethyl, ora pharmaceutically acceptable salt thereof.
 2. A compound of claim 1wherein X is a bond.
 3. A compound of claim 2 wherein n is
 0. 4. Acompound of claim 2 wherein each R₃ is hydrogen.
 5. A compound of claim2 wherein R₄ is alkyl
 6. A compound of claim 2 wherein R₂ is selectedfrom the group consisting of hydrogen, C₁₋₄ alkyl, and C₁₋₄ alkyl-O—C₁₋₄alkyl.
 7. A compound of claim 2 wherein the dashed bonds are absent. 8.A compound selected from the group consisting of:N-[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]benzenesulfonamide;N-[4-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]benzenesulfonamide;N-[4-(4-amino-2-hexyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]benzenesulfonamide;N-[4-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamide;N-[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamide;N-[4-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]benzenesulfonamide;N-[4-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamide;N-[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]methanesulfonamide;N-[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]benzenesulfonamide;N-[4-(4-amino-2-hexyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamide;N-{8-[4-amino-2-(2-methoxyethyl)-H-imidazo[4,5-c]quinolin-1-yl]octyl}benzenesulfonamide;N-{8-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]octyl}methanesulfonamide;N-[8-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)octyl]methanesulfonamide;N-[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]-5-(dimethylamino)naphthalene-1-sulfonamide;N-[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]-4-methylbenzenesulfonamide;N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}methanesulfonamide;N-[8-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)octyl]benzenesulfonamide;N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}benzenesulfonamide;N-[4-(4-amino-2-pentyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamide;N-[4-(4-amino-2-pentyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]benzenesulfonamide;N-[8-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)octyl]methanesulfonamide;N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}-4-methylbenzenesulfonamide;N-[4-(4-amino-2-pentyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamide;N-{3-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}methanesulfonamide;N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2,2-dimethylpropyl}methanesulfonamide;N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}-5-(dimethylamino)naphthalene-1-sulfonamide;N-[3-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]methanesulfonamide;N-{3-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl]propyl}methanesulfonamide;N-{3-[4-amino-2-(ethoxymethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl]propyl}methanesulfonamide;N-{3-[4-amino-2-(3-phenoxypropyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}methanesulfonamide;N-{4-[4-amino-2-(3-phenoxypropyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}methanesulfonamide;N-[4-(4-amino-2-methyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamidehydrochloride;N-[2-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]-4-methylbenzenesulfonamide;N-[2-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]methanesulfonamide;1-[4-(1,1-dioxidoisothiazolidin-2-yl)butyl]-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine;2-butyl-1-[4-(1,1-dioxidoisothiazolidin-2-yl)butyl]-1H-imidazo[4,5-c]quinolin-4-amine;N-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}methanesulfonamide;N-[4-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]ethanesulfonamide;1-(2-amino-2-methylpropyl)-1H-imidazo[4,5-c]quinoline-4-amine; andN-{4-[4-amino-2-(cyclopropylmethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}methanesulfonamide;or a pharmaceutically acceptable salt thereof.
 9. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof claim 1 and a pharmaceutically acceptable carrier.
 10. Apharmaceutical composition comprising a therapeutically effective amountof a compound of claim 2 and a pharmaceutically acceptable carrier. 11.A pharmaceutical composition comprising a therapeutically effectiveamount of a compound of claim 8 and a pharmaceutically acceptablecarrier.
 12. A method of inducing cytokine biosynthesis in an animalcomprising administering an effective amount of a compound of claim 1 tothe animal.
 13. A method of inducing cytokine biosynthesis in an animalcomprising administering an effective amount of a compound of claim 2 tothe animal.
 14. A method of inducing cytokine biosynthesis in an animalcomprising administering an effective amount of a compound of claim 8 tothe animal.